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Li M, Li D, Wang HY, Zhang W, Zhuo Z, Guo H, Liu J, Zhuo Y, Tang J, He J, Miao L. Leptin decreases Th17/Treg ratio to facilitate neuroblastoma via inhibiting long-chain fatty acid catabolism in tumor cells. Oncoimmunology 2025; 14:2460281. [PMID: 39902867 PMCID: PMC11796542 DOI: 10.1080/2162402x.2025.2460281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 01/05/2025] [Accepted: 01/24/2025] [Indexed: 02/06/2025] Open
Abstract
The exploration of therapeutic targets in neuroblastoma (NB), which needs more attempts, can benefit patients with high-risk NB. Based on metabolomic and transcriptomic data in mediastinal NB tissues, we found that the content of long-chain acylcarnitine (LCAC) was increased and positively associated with leptin expression in advanced NB. Leptin over-expression forced naïve CD4+ T cells to differentiate into Treg cells instead of Th17 cells, which benefited from NB cell proliferation, migration, and drug resistance. Mechanically, leptin in NB cells blunted the activity of carnitine palmitoyltransferase 2 (CPT2), the key enzyme for LCAC catabolism, by inhibiting sirtuin 3-mediated CPT2 deacetylation, which depresses oxidative phosphorylation (OXPHOS) for energy supply and increases lactic acid (LA) production from glycolysis to modulate CD4+ T cell differentiation. These findings highlight that excess leptin contributes to lipid metabolism dysfunction in NB cells and subsequently misdirects CD4+ T cell differentiation in tumor micro-environment (TME), indicating that targeting leptin could be a therapeutic strategy for retarding NB progression.
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Affiliation(s)
- Meng Li
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China
| | - Di Li
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China
| | - Hai-Yun Wang
- Department of Pathology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children’s Medical Center for South Central Region, Guangzhou, Guangdong, China
| | - Weixin Zhang
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China
| | - Zhenjian Zhuo
- Laboratory Animal Center, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Huiqin Guo
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China
| | - Jiabin Liu
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China
| | - Yue Zhuo
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jue Tang
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China
| | - Lei Miao
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China
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2
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Morita R, Ishikawa T, Doi T, Itani J, Sone D, Iwai N, Inoue K, Konishi H, Dohi O, Yoshida N, Shiozaki A, Uchiyama K, Takagi T, Fujiwara H, Konishi H, Itoh Y. Prognostic value of liver metastasis in patients with esophageal squamous cell carcinoma treated with nivolumab. Oncol Lett 2025; 29:145. [PMID: 39877058 PMCID: PMC11773300 DOI: 10.3892/ol.2025.14891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 10/28/2024] [Indexed: 01/31/2025] Open
Abstract
Nivolumab has been approved for unresectable recurrent advanced esophageal cancer. The present study aimed to provide real-world data on diverse patient profiles, including the elderly and those with poor performance status, while exploring therapeutic efficacy biomarkers. This retrospective study included 42 patients with esophageal cancer who received nivolumab after second- or later-line treatment at Kyoto Prefectural University of Medicine (Kyoto, Japan) from February 2020 to December 2021. The study evaluated real-world patient data for the outcomes, safety and clinical characteristics impacting efficacy. The median patient age was 70 years (range, 52-80), and 36 patients (85%) were male. A total of 22 patients (52%) were ≥70 years of age, and three (7%) had an Eastern Clinical Oncology Group Performance Status of 2, which was not included in the clinical trial. The response and disease control rates were 26 and 78%, respectively. With a median follow-up period of 7.9 months, the median progression-free survival and overall survival were 3.5 (95% CI, 2.0-6.0) and 19 (95% CI, 6.4-not reached) months, respectively. Patients with liver metastases had significantly worse progression-free survival and overall survival, while lung and lymph node metastases did not clearly impact nivolumab efficacy. Multivariate analysis revealed that liver metastases may predict both worse progression-free survival [hazard ratio (HR) 2.37; 95% CI, 1.07-5.24; P=0.03) and overall survival (HR, 2.75; 95% CI, 1.00-7.53; P=0.04). This study provided real-world evidence of nivolumab's favorable efficacy across diverse profiles, including the elderly and those with impaired performance status. No serious immune-related adverse events occurred and liver metastasis emerged as a predictive biomarker for nivolumab efficacy in esophageal squamous cell cancer.
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Affiliation(s)
- Ryuichi Morita
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Takeshi Ishikawa
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
- Oncology Unit, University Hospital of Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Toshifumi Doi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Junichiro Itani
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Daiki Sone
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Naoto Iwai
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Ken Inoue
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Osamu Dohi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Naohisa Yoshida
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Kazuhiko Uchiyama
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Tomohisa Takagi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Hideyuki Konishi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
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3
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Huang CJ, Liu GT, Yeh YC, Chung SY, Chang YC, Chiang NJ, Lu ML, Huang WN, Chen MH, Wang YC. Construction of hot tumor classification models in gastrointestinal cancers. J Transl Med 2025; 23:218. [PMID: 39984938 DOI: 10.1186/s12967-025-06230-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/11/2025] [Indexed: 02/23/2025] Open
Abstract
BACKGROUND Gastrointestinal (GI) cancers account for more than one-third of cancer-related mortality, and the prognosis for late-stage patients remains poor. Immunotherapy has been proven to extend the survival of patients at advanced stages; however, challenges persist in patient selection and overcoming drug resistance. Tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLS) in the tumor microenvironment (TME) have been found to be associated with anti-tumor immune responses. 'Hot tumors' with high levels of infiltration tend to respond better to immune checkpoint inhibitor (ICI) therapy, making them potential biomarkers for ICI treatment. METHODS To explore potential biomarkers for predicting immunotherapy response and prognosis in GI cancers, we downloaded the gene expression profiles of seven GI cancers from The Cancer Genome Atlas (TCGA) database and characterized their TME, classifying the samples into hot/cold tumor subgroups. Furthermore, we developed a computational framework to construct cancer-specific hot tumor classification models with only a few genes. External independent datasets and qPCR experiments were used to verify the performance of our few-gene models. RESULTS We constructed cancer-specific few-gene models to identify hot tumors for GI cancers with only two to nine genes. The results showed that B cells are important for hot tumor determination, and the identified hot tumors are significantly associated with TLS. They not only overexpress TLS marker genes but are also associated with the presence of TLS in whole-slide images. Further, a two-gene qPCR model was developed to effectively distinguish between hot and cold tumor subgroups in cholangiocarcinoma, providing an opportunity for stratifying patients with hot tumors in clinical settings. CONCLUSIONS In conclusion, our established few-gene models, which can be easily integrated into clinical practice, can distinguish hot and cold tumor subgroups, and may serve as potential biomarkers for predicting ICI response.
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Affiliation(s)
- Chien-Jung Huang
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Guan-Ting Liu
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Chen Yeh
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shin-Yi Chung
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yu-Chan Chang
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Nai-Jung Chiang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Meng-Lun Lu
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wei-Ning Huang
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ming-Huang Chen
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
| | - Yu-Chao Wang
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan.
- Digital Medicine and Smart Healthcare Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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4
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Xu Q, Hua X, Li B, Jiang B, Jin J, Wu R, Gu Y, Xu H, Cheng Q, Zhu S, Zhang F, Lv T, Song Y. Intrinsic STING of CD8 + T cells regulates self-metabolic reprogramming and memory to exert anti-tumor effects. Cell Commun Signal 2025; 23:99. [PMID: 39972350 DOI: 10.1186/s12964-025-02069-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 01/28/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Our team has previously found that the stimulator of interferon genes (STING) plays a more significant anti-tumor role in host immune cells than in tumor cells. Although STING is necessary for CD8 + T cells to exert immunological activity, its effect on CD8 + T cells remains debatable. In this study, we used both in vitro and in vivo models to explore the metabolic effects of STING on CD8 + T cells. METHODS Peripheral blood lymphocytes were procured from non-small cell lung cancer (NSCLC) patients receiving anti-PD-1 therapy to investigate the correlation between STING expression levels, CD8 + T-cell subsets, and immunotherapy efficacy. STING knockout (STING-KO) mice were used for in vivo studies. RNA-seq, seahorse, flow cytometry, electron microscopy, qPCR, immunofluorescence, western blotting, and immunoprecipitation were performed to explore the underlying mechanisms of STING in regulating CD8 + T cell function. RESULTS We discovered that the expression level of STING in immune cells exhibited a significant correlation with immunotherapy efficacy, as well as with the proportion of central memory CD8 + T cells. Moreover, we found that the loss of the STING gene results in a reduction in the number of mitochondria and a change in the metabolic pathway selection, thereby inducing excessive glycolysis in CD8 + T cells. This excessive glycolysis generates high levels of lactate, which further inhibits IFN-γ secretion and impacts memory T cell differentiation. Correcting the glycolysis disorder partially restored function and IFN-γ secretion, rescued the central memory CD8 + T subset, and improved immunotherapy in STING-KO mice. This provides a new treatment strategy for patients with low STING expression and a poor response to immunotherapy. CONCLUSION Intrinsic STING of CD8 + T cells affects their function through the HK2/Lactate/IFN-γ axis and affects memory differentiation by regulating glycolysis.
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Affiliation(s)
- Qiuli Xu
- School of Medicine, Southeast University, Nanjing, Jiangsu, 210002, China
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing, Jiangsu, 210002, China
| | - Xin Hua
- Department of Geriatric Medicine, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
| | - Bingbing Li
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, School of Medicine, Nanjing University of Traditional Chinese Medicine Southeast University, #305 East Zhongshan Road, Nanjing, Jiangsu, 210002, China
| | - Bei Jiang
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, School of Medicine, Nanjing University of Traditional Chinese Medicine Southeast University, #305 East Zhongshan Road, Nanjing, Jiangsu, 210002, China
| | - Jiajia Jin
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing, Jiangsu, 210002, China
| | - Ranpu Wu
- School of Medicine, Southeast University, Nanjing, Jiangsu, 210002, China
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing, Jiangsu, 210002, China
| | - Yanli Gu
- Department of Respiratory and Critical Care Medicine People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, China
| | - Hao Xu
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing, Jiangsu, 210002, China
- Nanjing Medical University, Nanjing, Jiangsu, 210002, China
| | - Qinpei Cheng
- Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China
| | - Suhua Zhu
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing, Jiangsu, 210002, China
| | - Fang Zhang
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing, Jiangsu, 210002, China
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, School of Medicine, Nanjing University of Traditional Chinese Medicine Southeast University, #305 East Zhongshan Road, Nanjing, Jiangsu, 210002, China
| | - Tangfeng Lv
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, School of Medicine, Nanjing University of Traditional Chinese Medicine Southeast University, #305 East Zhongshan Road, Nanjing, Jiangsu, 210002, China.
| | - Yong Song
- School of Medicine, Southeast University, Nanjing, Jiangsu, 210002, China.
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing, Jiangsu, 210002, China.
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5
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Bando H, Kumagai S, Kotani D, Mishima S, Irie T, Itahashi K, Tanaka Y, Habu T, Fukaya S, Kondo M, Tsushima T, Hara H, Kadowaki S, Kato K, Chin K, Yamaguchi K, Kageyama SI, Hojo H, Nakamura M, Tachibana H, Wakabayashi M, Fukui M, Fuse N, Koyama S, Mano H, Nishikawa H, Shitara K, Yoshino T, Kojima T. Atezolizumab following definitive chemoradiotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma - a multicenter phase 2 trial (EPOC1802). NATURE CANCER 2025:10.1038/s43018-025-00918-1. [PMID: 39972105 DOI: 10.1038/s43018-025-00918-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 01/21/2025] [Indexed: 02/21/2025]
Abstract
Platinum-based definitive chemoradiotherapy (dCRT) is the standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) that invades the aorta, vertebral body or trachea; however, complete response rates remain low (11-25%), leading to poor survival. To evaluate the additive efficacy of the anti-PD-L1 antibody drug atezolizumab, we conducted a phase 2, multicenter, single-arm trial of 1 year of atezolizumab treatment following dCRT in 40 patients with unresectable locally advanced ESCC recruited from seven Japanese centers (UMIN000034373). The confirmed complete response (cCR) rate (primary end point) of the first consecutive 38 patients was 42.1% (90% CI 28.5-56.7%). Regarding the secondary end points, the median progression-free survival and 12-month progression-free survival rates of all 40 patients were 3.2 months and 29.6%, respectively, and the preliminary median overall survival with short-term follow-up and 12-month overall survival rate were 31.0 months and 65.8%, respectively. Other secondary end points evaluated included the cCR rate determined by an investigator's assessment in the locoregionally recurrent ESCC cohort, cCR rate determined by central assessment, overall response rate and incidence of adverse events. No treatment-related death occurred during the study. Atezolizumab monotherapy after dCRT resulted in a promising cCR rate, although long-term survival data are required.
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Affiliation(s)
- Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
| | - Shogo Kumagai
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Kashiwa, Japan
- Division of Cellular Signaling, Research Institute, National Cancer Center, Tokyo, Japan
| | - Daisuke Kotani
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Saori Mishima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takuma Irie
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Kashiwa, Japan
| | - Kota Itahashi
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Kashiwa, Japan
| | - Yosuke Tanaka
- Division of Cellular Signaling, Research Institute, National Cancer Center, Tokyo, Japan
| | - Takumi Habu
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Kashiwa, Japan
- Department of Gastric Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Sayuri Fukaya
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Kashiwa, Japan
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaki Kondo
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Kashiwa, Japan
- Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takahiro Tsushima
- Division of Gastrointestinal Oncology Shizuoka Cancer Center, Shizuoka, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Ken Kato
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Keisho Chin
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shun-Ichiro Kageyama
- Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hidehiro Hojo
- Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masaki Nakamura
- Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hidenobu Tachibana
- Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masashi Wakabayashi
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Makoto Fukui
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Nozomu Fuse
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shohei Koyama
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Kashiwa, Japan
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiroyuki Mano
- Division of Cellular Signaling, Research Institute, National Cancer Center, Tokyo, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Kashiwa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Kindai University Faculty of Medicine, Osaka, Japan
| | - Takashi Kojima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
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Muraoka S, Baba T, Akazawa T, Katayama KI, Kusumoto H, Yamashita S, Kohjimoto Y, Iwabuchi S, Hashimoto S, Hara I, Inoue N. Tumor-derived lactic acid promotes acetylation of histone H3K27 and differentiation of IL-10-producing regulatory B cells through direct and indirect signaling pathways. Int J Cancer 2025; 156:840-852. [PMID: 39482832 DOI: 10.1002/ijc.35229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/02/2024] [Accepted: 10/08/2024] [Indexed: 11/03/2024]
Abstract
Tumor cells are known to enhance glycolysis, even under normoxic conditions, via the Warburg effect, producing excess lactic acid in the tumor microenvironment. Lactic acid enhances the IL-23/IL-17 pathway and induces chronic inflammation. The acidic microenvironment formed by lactic acid suppresses immune cell proliferation and activation. In the present study, we clarified that lactic acid had two novel activities for immune cells. First, lactic acid specifically enhanced acetylation at lysine 27 of histone H3 (H3K27ac) in splenic B cells and monocytes/macrophages, and this epigenetically up-regulates the expression of genes. Acetylation and methylation of other residues of histone H3 were rarely induced. Second, lactic acid induced a particularly-marked enhancement of Il10 gene expression in B cells, leading to an increase in IL-10-producing regulatory B (Breg) cells. Furthermore, two pathways should be involved in both the enhancement of H3K27ac and the induction of Breg cells by lactic acid: a direct pathway that enhances the CD40 signal in B cells, and an indirect pathway that affects B cells by activating the exchange protein directly activated by cAMP (EPAC) 1/2 in non-B cells. In tumor-bearing mice, the levels of H3K27ac of tumor-infiltrating B cells were significantly higher than splenic B cells and were suppressed by intraperitoneal injection of the EPAC1/2 inhibitor. In conclusion, tumor-derived lactic acid increases H3K27ac and IL-10-producing Breg cells, causing the suppression of anti-tumor immunity.
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Affiliation(s)
- Satoshi Muraoka
- Department of Urology, Wakayama Medical University, Wakayama, Japan
| | - Takashi Baba
- Department of Molecular Genetics, Wakayama Medical University, Wakayama, Japan
| | - Takashi Akazawa
- Department of Cancer Drug Discovery and Development, Research Center, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan
| | - Kei-Ichi Katayama
- Department of Molecular Genetics, Wakayama Medical University, Wakayama, Japan
| | - Hiroki Kusumoto
- Department of Urology, Wakayama Medical University, Wakayama, Japan
| | | | - Yasuo Kohjimoto
- Department of Urology, Wakayama Medical University, Wakayama, Japan
| | - Sadahiro Iwabuchi
- Department of Molecular Pathophysiology, Wakayama Medical University, Wakayama, Japan
| | - Shinichi Hashimoto
- Department of Molecular Pathophysiology, Wakayama Medical University, Wakayama, Japan
| | - Isao Hara
- Department of Urology, Wakayama Medical University, Wakayama, Japan
| | - Norimitsu Inoue
- Department of Molecular Genetics, Wakayama Medical University, Wakayama, Japan
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7
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Chen J, Huang Z, Chen Y, Tian H, Chai P, Shen Y, Yao Y, Xu S, Ge S, Jia R. Lactate and lactylation in cancer. Signal Transduct Target Ther 2025; 10:38. [PMID: 39934144 DOI: 10.1038/s41392-024-02082-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 10/07/2024] [Accepted: 11/18/2024] [Indexed: 02/13/2025] Open
Abstract
Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings, particularly in intricate conditions such as cancer. Specifically, lactate has been demonstrated to be pivotal in molding the tumor microenvironment (TME) through its effects on different cell populations. Within tumor cells, lactate impacts cell signaling pathways, augments the lactate shuttle process, boosts resistance to oxidative stress, and contributes to lactylation. In various cellular populations, the interplay between lactate and immune cells governs processes such as cell differentiation, immune response, immune surveillance, and treatment effectiveness. Furthermore, communication between lactate and stromal/endothelial cells supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, and drug resistance. Focusing on lactate production and transport, specifically through lactate dehydrogenase (LDH) and monocarboxylate transporters (MCT), has shown promise in the treatment of cancer. Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy, leading to a synergistic therapeutic effect when combined with immunotherapy. The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism, highlighting the Heel of Achilles for cancer treatment.
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Affiliation(s)
- Jie Chen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Ziyue Huang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Ya Chen
- Department of Radiology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
| | - Hao Tian
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Peiwei Chai
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Yongning Shen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
| | - Yiran Yao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Shiqiong Xu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China.
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China.
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China.
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8
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Wang Z, Wu M, Jiang Y, Zhou J, Chen S, Wang Q, Sun H, Deng Y, Zhou Z, Sun M. Biomimetic calcium-chelation nanoparticles reprogram tumor metabolism to enhance antitumor immunity. J Control Release 2025; 380:362-374. [PMID: 39832746 DOI: 10.1016/j.jconrel.2025.01.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 01/14/2025] [Accepted: 01/17/2025] [Indexed: 01/22/2025]
Abstract
Metabolic reprogramming within the tumor microenvironment poses a significant obstacle to the therapeutic efficacy of antitumor immunity. Here, inspired by the diverse programme of cholesterol metabolism between tumor and immune cells, a biocompatible carboxy-modified cyclodextrin carrier equipped with a biomimetic surface was developed to encapsulate FX11 and Avasimibe (RM-CDC@FX11&Ava) for synergistic antitumor metabolic therapy and immunotherapy. Through the manipulation of calcium levels using poly-carboxylic compounds to initiate cholesterol biosynthesis, RM-CDC@FX11&Ava dynamically regulates glycolysis and blocks cholesterol esterification to navigate metabolic reprogramming. The resultant cholesterol augmentation triggered by RM-CDC@FX11&Ava could not only specifically induce 34.3 % tumor cell apoptosis but also promote 57.8 % dendritic cell maturation for antigen presentation and improve the effector function of T cells. Furthermore, the tumor immunosuppressive microenvironment was also reprogrammed by impairing Treg cells through the blockade of lactic acid. As a result, RM-CDC@FX11&Ava showed superior antitumor efficacy in mastadenoma and melanoma models.
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Affiliation(s)
- Zheng Wang
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Ming Wu
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Yingmeng Jiang
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Junjie Zhou
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Sai Chen
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Qizhi Wang
- State Key Laboratory of Natural Medicines, Key laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Honghao Sun
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Yueyang Deng
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Zhanwei Zhou
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
| | - Minjie Sun
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
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9
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Li G, Li S, Jiang Y, Chen T, An Z. Unleashing the Power of immune Checkpoints: A new strategy for enhancing Treg cells depletion to boost antitumor immunity. Int Immunopharmacol 2025; 147:113952. [PMID: 39764997 DOI: 10.1016/j.intimp.2024.113952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 12/22/2024] [Accepted: 12/24/2024] [Indexed: 01/29/2025]
Abstract
Regulatory T (Treg) cells, immunosuppressive CD4+ T cells, can impede anti-tumor immunity, complicating cancer treatment. Since their discovery, numerous studies have been dedicated to understand Treg cell biology, with a focus on checkpoint pathways' role in their generation and function. Immune checkpoints, such as PD-1/PD-L1, CTLA-4, TIGIT, TIM-3, and OX40, are pivotal in controlling Treg cell expansion and activity in the tumor microenvironment (TME), affecting their ability to suppress immune responses. This review examines the complex relationship between these checkpoints and Tregs in the TME, and how they influence tumor immunity. We also discuss the therapeutic potential of targeting these checkpoints to enhance anti-tumor immunity, including the use of immune checkpoint blockade (ICB) therapies and novel approaches such as CCR8-targeted therapies. Understanding the interaction between immune checkpoints and Treg cells can lead to more effective immunotherapeutic strategies, such as combining CCR8-targeted therapies with immune checkpoint inhibitors, to improve patient outcomes in cancer treatment.
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Affiliation(s)
- Guoxin Li
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China; Key Laboratory of Tooth Development and Bone Remodeling of Jilin Province, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Siqi Li
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Yilin Jiang
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Tao Chen
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Zhengwen An
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China; Key Laboratory of Tooth Development and Bone Remodeling of Jilin Province, School and Hospital of Stomatology, Jilin University, Changchun, China.
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10
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Li G, Wang Z, Guo Y, Ni C, Gao Y, Xu K, Xiao T, Shi X, Shen M. Copper-doped layered double hydroxides co-deliver proteins/drugs for cascaded chemodynamic/immunotherapy via dual regulation of tumor metabolism. Acta Biomater 2025:S1742-7061(25)00089-3. [PMID: 39921184 DOI: 10.1016/j.actbio.2025.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/17/2025] [Accepted: 02/04/2025] [Indexed: 02/10/2025]
Abstract
We report here a Cu2+-doped layered double hydroxide (LDH) nanoplatform to load both monocarboxylate transporter inhibitor diclofenac (DC) and lactate oxidase (LOX) for dual modulation of tumor lactate and redox metabolisms to activate immunotherapy through enhanced Cu-mediated chemodynamic therapy (CDT) of tumors. The formed LDH-DC-LOX nanoparticles with a diameter of 55 nm are stable, can be effectively taken up by cancer cells to regulate lactate through both LOX-mediated catalytic conversion and DC-enabled inhibition of extracellular efflux of lactate, and can exert redox metabolism through CDT via Cu2+-mediated glutathione (GSH) depletion and Fenton-like reaction with hydrogen peroxide (H2O2) that can be further accumulated via LOX-mediated catalysis. The major advantage of the developed LDH-DC-LOX nanoparticles lies in the therapeutic synergy and cascade that can be achieved through the loaded DC and LOX for enhanced tumor lactate metabolism regulation, for enhanced Cu-mediated CDT and redox metabolism regulation, and for activation of immunotherapy that can further enhances the Cu2+-mediated CDT effect. The developed LDH nanoplatform demonstrated here for effective murine breast tumor treatment provides a new paradigm for dual regulation of lactate and redox metabolisms that may enable synergistic and cascaded combination therapy of different cancer types. STATEMENT OF SIGNIFICANCE: Targeting the tumor microenvironment (TME) to alter tumor metabolic pathways represents a promising strategy for next-generation cancer therapy. Herein, a copper-doped layered double hydroxide (LDH) nanoplatform is developed to co-deliver both diclofenac (DC) and lactate oxidase (LOX) to tumor cells for efficient dual regulation of tumor lactate and redox metabolisms, resulting in synergistic and cascaded chemodynamic therapy/immunotherapy of breast tumors. The developed LDH-DC-LOX nanoparticles can release Cu2+ and DC under an acidic TME, and can act in synergy to reduce TME lactate and generate H2O2, thus modulating redox metabolism and activating anticancer immunotherapy. The secreted cytokine IFN-γ after activation of antitumor immune responses can further mediate enhanced chemodynamic therapy effect through downregulation of cystine/glutamate transporter SLC7A11 to suppress GSH synthesis.
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Affiliation(s)
- Gaoming Li
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Zhiqiang Wang
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Yunqi Guo
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Cheng Ni
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Yue Gao
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Kaibing Xu
- Research Center for Analysis and Measurement, Donghua University, Shanghai 201620, China
| | - Tingting Xiao
- Institute of Frontier Medical Technology, College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China
| | - Xiangyang Shi
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China; CQM-Centro de Química da Madeira, Universidade da Madeira, Campus Universitário da Penteada, Funchal 9020-105, Portugal.
| | - Mingwu Shen
- State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China.
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11
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Gorría T, Sierra-Boada M, Rojas M, Figueras C, Marin S, Madurga S, Cascante M, Maurel J. Metabolic Singularities in Microsatellite-Stable Colorectal Cancer: Identifying Key Players in Immunosuppression to Improve the Immunotherapy Response. Cancers (Basel) 2025; 17:498. [PMID: 39941865 PMCID: PMC11815897 DOI: 10.3390/cancers17030498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/26/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Although immune checkpoint inhibitor (ICI) therapy is currently the standard of care in microsatellite-unstable (MSI) metastatic colorectal cancer (CRC), ICI therapy, alone or in combination with other therapies, is not a treatment approach in microsatellite-stable (MSS) CRC, which is present in 95% of patients. In this review, we focus on metabolic singularities-at the transcriptomic (either bulk or single cell), proteomic, and post-translational modification levels-that induce immunosuppression in cancer and specifically in MSS CRC. First, we evaluate the current efficacy of ICIs in limited and metastatic disease in MSS CRC. Second, we discuss the latest findings on the potential biomarkers for evaluating ICI efficacy in MSS CRC using strict REMARK criteria. Third, we review the current evidence on metabolic patterns in CRC tumors and immune cell metabolism to advance our understanding of metabolic crosstalk and to pave the way for the development of combination strategies to enhance ICI efficacy.
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Affiliation(s)
- Teresa Gorría
- Medical Oncology Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; (T.G.); (M.R.); (C.F.)
- Translational Genomics and Targeted Therapies in Solid Tumors, Agustí Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
- Medicine Department, University of Barcelona, 08036 Barcelona, Spain
| | - Marina Sierra-Boada
- Medical Oncology Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain;
| | - Mariam Rojas
- Medical Oncology Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; (T.G.); (M.R.); (C.F.)
| | - Carolina Figueras
- Medical Oncology Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; (T.G.); (M.R.); (C.F.)
| | - Silvia Marin
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08036 Barcelona, Spain;
- Institute of Biomedicine of University of Barcelona (IBUB), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Sergio Madurga
- Department of Material Science and Physical Chemistry, Research Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, 08028 Barcelona, Spain;
| | - Marta Cascante
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08036 Barcelona, Spain;
- Institute of Biomedicine of University of Barcelona (IBUB), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Joan Maurel
- Medical Oncology Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; (T.G.); (M.R.); (C.F.)
- Translational Genomics and Targeted Therapies in Solid Tumors, Agustí Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
- Medicine Department, University of Barcelona, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
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12
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Yang C, Zha M, Li L, Qiao J, Kwok LY, Wang D, Chen Y. Bifidobacterium animalis ssp. lactis BX-245-fermented milk alleviates tumor burden in mice with colorectal cancer. J Dairy Sci 2025; 108:1211-1226. [PMID: 39694256 DOI: 10.3168/jds.2024-25614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 10/08/2024] [Indexed: 12/20/2024]
Abstract
Colorectal cancer (CRC) arises from the accumulation of abnormal mutations in colorectal cells during prolonged inflammation. This study aimed to investigate the potential of probiotic fermented milk containing the probiotic strain, Bifidobacterium animalis ssp. lactis BX-245 (BX-245), in alleviating tumor burden in CRC mice induced by azoxymethane and dextran sodium sulfate. The study monitored changes in tumor size and number, gut microbiota, metabolomics, and inflammation levels before and after the intervention. Our findings indicate that intragastric administration of BX245-fermented milk effectively modulated the intratumor microbiota, as well as the gut microbiota and its metabolism. We also observed a decreased relative abundance of intratumor Akkermansia in the CRC mice, while the intratumor Parabacteroides exhibited a significant positive correlation with tumor number and weight. Moreover, administering BX245-fermented milk significantly reduced gut barrier permeability, alleviated gut barrier damage, and increased serum IL-2 and IFN-γ levels compared with the ordinary fermented milk group. Collectively, our data suggest that administering probiotic fermented milk containing specific functional strains such as BX245 could result in a reduction in tumor burden in CRC mice. Conversely, ordinary fermented milk did not show the same tumor-inhibiting effects. The current results are preliminary, and further confirmation is necessary to establish the causal relationship among probiotic milk, changes in gut microbiota, and disease alleviation.
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Affiliation(s)
- Chengcong Yang
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Inner Mongolia Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China
| | - Musu Zha
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Inner Mongolia Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China
| | - Lu Li
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Inner Mongolia Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China
| | - Jiaqi Qiao
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Inner Mongolia Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China
| | - Lai-Yu Kwok
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Inner Mongolia Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China
| | - Dandan Wang
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Inner Mongolia Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China
| | - Yongfu Chen
- Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China; Inner Mongolia Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia 010018, China.
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13
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Härm J, Fan YT, Brenner D. Navigating the metabolic landscape of regulatory T cells: from autoimmune diseases to tumor microenvironments. Curr Opin Immunol 2025; 92:102511. [PMID: 39674060 DOI: 10.1016/j.coi.2024.102511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 12/16/2024]
Abstract
Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, playing crucial roles in modulating autoimmune conditions and contributing to the suppressive tumor microenvironment. Their cellular metabolism governs their generation, stability, proliferation, and suppressive function. Enhancing Treg metabolism to boost their suppressive function offers promising therapeutic potential for alleviating inflammatory symptoms in autoimmune diseases. Conversely, inhibiting Treg metabolism to reduce their suppressive function can enhance the efficacy of traditional immunotherapy in cancer patients. This review explores recent advances in targeting Treg metabolism in autoimmune diseases and the metabolic adaptations of Tregs within the tumor microenvironment that increase their immunosuppressive function.
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Affiliation(s)
- Janika Härm
- Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Yu-Tong Fan
- Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Dirk Brenner
- Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
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14
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Zeng Y, Huang Y, Tan Q, Peng L, Wang J, Tong F, Dong X. Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review). Mol Med Rep 2025; 31:48. [PMID: 39670310 DOI: 10.3892/mmr.2024.13413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 11/01/2024] [Indexed: 12/14/2024] Open
Abstract
Metabolic reprogramming is a prominent characteristic of tumor cells, evidenced by heightened secretion of lactate, which is linked to tumor progression. Furthermore, the accumulation of lactate in the tumor microenvironment (TME) influences immune cell activity, including the activity of macrophages, dendritic cells and T cells, fostering an immunosuppressive milieu. Anti‑programmed cell death protein 1 (PD‑1)/programmed death‑ligand 1 (PD‑L1) therapy is associated with a prolonged survival time of patients with non‑small cell lung cancer. However, some patients still develop resistance to anti‑PD‑1/PD‑L1 therapy. Lactate is associated with resistance to anti‑PD‑1/PD‑L1 therapy. The present review summarizes what is known about lactate metabolism in tumor cells and how it affects immune cell function. In addition, the present review emphasizes the relationship between lactate secretion and immunotherapy resistance. The present review also explores the potential for targeting lactate within the TME to enhance the efficacy of immunotherapy.
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Affiliation(s)
- Yi Zeng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yu Huang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Qiaoyun Tan
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Ling Peng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jian Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Fan Tong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xiaorong Dong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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15
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Yu D, Zhong Q, Wang Y, Yin C, Bai M, Zhu J, Chen J, Li H, Hong W. Lactylation: The metabolic accomplice shaping cancer's response to radiotherapy and immunotherapy. Ageing Res Rev 2025; 104:102670. [PMID: 39864560 DOI: 10.1016/j.arr.2025.102670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 01/09/2025] [Accepted: 01/22/2025] [Indexed: 01/28/2025]
Abstract
Protein lactylation, an emerging post-translational modification, is providing new insights into tumor biology and challenging our current understanding of cancer mechanisms. Our review illuminates the intricate roles of lactylation in carcinogenesis, tumor progression, and therapeutic responses, positioning it as a critical linchpin connecting metabolic reprogramming, epigenetic modulation, and treatment outcomes. We provide an in-depth analysis of lactylation's molecular mechanisms and its far-reaching impact on cell cycle regulation, immune evasion strategies, and therapeutic resistance within the complex tumor microenvironment. Notably, this review dissects the paradoxical nature of lactylation in cancer immunotherapy and radiotherapy. While heightened lactylation can foster immune suppression and radioresistance, strategically targeting lactylation cascades opens innovative avenues for amplifying the efficacy of current treatment paradigms. We critically evaluate lactylation's potential as a robust diagnostic and prognostic biomarker and explore frontier therapeutic approaches targeting lactylation. The synergistic integration of multi-omics data and artificial intelligence in lactylation research is catalyzing significant strides towards personalized cancer management. This review not only consolidates current knowledge but also charts a course for future investigations. Key research imperatives include deciphering tumor-specific lactylation signatures, optimizing synergistic strategies combining lactylation modulation with immune checkpoint inhibitors and radiotherapy, and comprehensively assessing the long-term physiological implications of lactylation intervention. As our understanding of lactylation's pivotal role in tumor biology continues to evolve, this burgeoning field promises to usher in transformative advancements in cancer diagnosis, treatment modalitie.
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Affiliation(s)
- Danqing Yu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Qingping Zhong
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Yanlin Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310000, China
| | - Chang Yin
- Nursing Department, Shanghai Sixth People's Hospital, Shanghai 200233, China
| | - Minghua Bai
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Ji Zhu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Jinggang Chen
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
| | - Huaming Li
- Department of Gastroenterology, Hangzhou Third Peoples Hospital, Hangzhou 310000, China.
| | - Weifeng Hong
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
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16
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Iozzo M, Comito G, Ippolito L, Sandrini G, Pardella E, Pranzini E, Capone M, Madonna G, Ascierto PA, Chiarugi P, Giannoni E. Sex-related changes in lactate dehydrogenase A expression differently impact the immune response in melanoma. FEBS J 2025. [PMID: 39888245 DOI: 10.1111/febs.17423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 11/08/2024] [Accepted: 01/20/2025] [Indexed: 02/01/2025]
Abstract
Melanoma is more aggressive in male patients than female ones and this is associated with sexual dimorphism in immune responses. Taking into consideration the impact tumour metabolic alterations in affecting the immune landscape, we aimed to investigate the effect of the sex-dependent metabolic profile of melanoma in re-shaping immune composition. Melanoma is characterised by Warburg metabolism, and secreted lactate has emerged as a key driver in the establishment of an immunosuppressive environment. Here, we identified lactate dehydrogenase A (LDH-A) as a crucial player in modulating sex-related differences in melanoma immune responses, both in vitro and in patient-derived specimens. LDH-A is associated with higher lactate secretion in male melanoma cells, which leads to a significant enrichment in pro-tumoural regulatory T cells (Treg) with a concurrent decrease in the number and activity of anti-tumour CD8+ T cells. Remarkably, pharmacological and genetic impairment of LDH-A in male melanoma cells normalises Treg and CD8+ infiltration. In keeping with this, in vivo pharmacological targeting of LDH-A in melanoma-bearing male mice impairs tumour growth and lung colonisation, with a concomitant modulation of Treg and CD8+ T cells infiltration. Taken together, our findings highlight the sex-related differences promoted by LDH-A in immune reshaping in melanoma, and suggest that therapeutic targeting of LDH-A could be leveraged as an effective strategy to abolish the sex-gap in melanoma progression.
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Affiliation(s)
- Marta Iozzo
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Giuseppina Comito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Luigi Ippolito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Giada Sandrini
- Institute of Oncology Research (IOR), Università della Svizzera Italiana (USI), Bellinzona, Switzerland
| | - Elisa Pardella
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Erica Pranzini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Mariaelena Capone
- Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Gabriele Madonna
- Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | | | - Paola Chiarugi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Elisa Giannoni
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
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17
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Ricci JE. Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets. Cell Rep 2025; 44:115206. [PMID: 39798090 DOI: 10.1016/j.celrep.2024.115206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/04/2024] [Accepted: 12/23/2024] [Indexed: 01/15/2025] Open
Abstract
Metabolic reprogramming in both immune and cancer cells plays a crucial role in the antitumor immune response. Recent studies indicate that cancer metabolism not only sustains carcinogenesis and survival via altered signaling but also modulates immune cell function. Metabolic crosstalk within the tumor microenvironment results in nutrient competition and acidosis, thereby hindering immune cell functionality. Interestingly, immune cells also undergo metabolic reprogramming that enables their proliferation, differentiation, and effector functions. This review highlights the regulation of antitumor immune responses through metabolic reprogramming in cancer and immune cells and explores therapeutic strategies that target these metabolic pathways in cancer immunotherapy, including using chimeric antigen receptor (CAR)-T cells. We discuss innovative combinations of immunotherapy, cellular therapies, and metabolic interventions that could optimize the efficacy of existing treatment protocols.
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Affiliation(s)
- Jean-Ehrland Ricci
- Université Côte d'Azur, INSERM, C3M, Nice, France; Équipe labellisée LIGUE Contre le Cancer, Nice, France.
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18
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Gong Q, Song X, Tong Y, Huo L, Zhao X, Han Y, Shen W, Ru J, Shen X, Liang C. Recent advances of anti-tumor nano-strategies via overturning pH gradient: alkalization and acidification. J Nanobiotechnology 2025; 23:42. [PMID: 39849540 PMCID: PMC11761731 DOI: 10.1186/s12951-025-03134-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 01/19/2025] [Indexed: 01/25/2025] Open
Abstract
The acidic tumor microenvironment, a hallmark of many solid tumors, is primarily induced by the high glycolytic rate of tumor cells. To avoid acidosis, tumor cells ingeniously maintain an acidic extracellular pH while keeping a relatively alkaline intracellular pH. Overturning the unique pH gradient of tumor cells has exhibited to be a viable approach for cancer therapy. In this review, the formation and regulatory mechanisms of the acidic microenvironment in solid tumors will be firstly outlined. Subsequently, we will comprehensively summarize the latest advancements in anti-tumor therapy via using nanomedicines to manipulate the tumor pH gradient, including acidifying intracellular environment and alkalizing extracellular environment. Following this, we will discuss the future potential of strategies employing nanomedicines to reverse tumor pH gradient. This review aims to foster research on therapeutic approaches targeting the pH regulation of solid tumors and holds an optimistic outlook for the future development of this field.
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Affiliation(s)
- Qiufang Gong
- Institute for Advanced Research, Cixi Biomedical Research Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xuejiao Song
- School of Physical and Mathematical Sciences, Nanjing Tech University (Nanjing Tech), Nanjing, 211816, China.
| | - Yao Tong
- Institute for Advanced Research, Cixi Biomedical Research Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Lixuan Huo
- Institute for Advanced Research, Cixi Biomedical Research Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xuefen Zhao
- Institute for Advanced Research, Cixi Biomedical Research Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Yingying Han
- Institute for Advanced Research, Cixi Biomedical Research Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Wei Shen
- Institute for Advanced Research, Cixi Biomedical Research Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jiaxi Ru
- Institute for Advanced Research, Cixi Biomedical Research Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xian Shen
- Institute for Advanced Research, Cixi Biomedical Research Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Chao Liang
- Institute for Advanced Research, Cixi Biomedical Research Institute, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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19
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Cote AL, Munger CJ, Ringel AE. Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions. Cell Rep 2025; 44:115234. [PMID: 39862435 DOI: 10.1016/j.celrep.2025.115234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/24/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
Tumors are inherently embedded in systemic physiology, which contributes metabolites, signaling molecules, and immune cells to the tumor microenvironment. As a result, any systemic change to host metabolism can impact tumor progression and response to therapy. In this review, we explore how factors that affect metabolic health, such as diet, obesity, and exercise, influence the interplay between cancer and immune cells that reside within tumors. We also examine how metabolic diseases influence cancer progression, metastasis, and treatment. Finally, we consider how metabolic interventions can be deployed to improve immunotherapy. The overall goal is to highlight how metabolic heterogeneity in the human population shapes the immune response to cancer.
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Affiliation(s)
- Andrea L Cote
- Ragon Institute of Mass General, MIT, and Harvard, 600 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
| | - Chad J Munger
- Ragon Institute of Mass General, MIT, and Harvard, 600 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
| | - Alison E Ringel
- Ragon Institute of Mass General, MIT, and Harvard, 600 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
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20
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Lu Y, Wang Y, Ruan T, Wang Y, Ju L, Zhou M, Liu L, Yao D, Yao M. Immunometabolism of Tregs: mechanisms, adaptability, and therapeutic implications in diseases. Front Immunol 2025; 16:1536020. [PMID: 39917294 PMCID: PMC11798928 DOI: 10.3389/fimmu.2025.1536020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 01/06/2025] [Indexed: 02/09/2025] Open
Abstract
Immunometabolism is an emerging field that explores the intricate interplay between immune cells and metabolism. Regulatory T cells (Tregs), which maintain immune homeostasis in immunometabolism, play crucial regulatory roles. The activation, differentiation, and function of Tregs are influenced by various metabolic pathways, such as the Mammalian targets of rapamycin (mTOR) pathway and glycolysis. Correspondingly, activated Tregs can reciprocally impact these metabolic pathways. Tregs also possess robust adaptive capabilities, thus enabling them to adapt to various microenvironments, including the tumor microenvironment (TME). The complex mechanisms of Tregs in metabolic diseases are intriguing, particularly in conditions like MASLD, where Tregs are significantly upregulated and contribute to fibrosis, while in diabetes, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), they show downregulation and reduced anti-inflammatory capacity. These phenomena suggest that the differentiation and function of Tregs are influenced by the metabolic environment, and imbalances in either can lead to the development of metabolic diseases. Thus, moderate differentiation and inhibitory capacity of Tregs are critical for maintaining immune system balance. Given the unique immunoregulatory abilities of Tregs, the development of targeted therapeutic drugs may position them as novel targets in immunotherapy. This could contribute to restoring immune system balance, resolving metabolic dysregulation, and fostering innovation and progress in immunotherapy.
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21
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Chen L, Yang J, Jia L, Wei X, Wang H, Liu Z, Jiang S, Li P, Zhou Y, Wang H, Si N, Bian B, Zhao Q, Zhao H. MOF-derived intelligent arenobufagin nanocomposites with glucose metabolism inhibition for enhanced bioenergetic therapy and integrated photothermal-chemodynamic-chemotherapy. J Nanobiotechnology 2025; 23:19. [PMID: 39819479 PMCID: PMC11740360 DOI: 10.1186/s12951-024-03084-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 12/26/2024] [Indexed: 01/19/2025] Open
Abstract
Bioenergetic therapy based on tumor glucose metabolism is emerging as a promising therapeutic modality. To overcome the poor bioavailability and toxicity of arenobufagin (ArBu), a MOF-derived intelligent nanosystem, ZIAMH, was designed to facilitate energy deprivation by simultaneous interventions of glycolysis, OXPHOS and TCA cycle. Herein, zeolitic imidazolate framework-8 was loaded with ArBu and indocyanine green, encapsulated within metal-phenolic networks for chemodynamic therapy and hyaluronic acid modification for tumor targeting. ZIAMH nanoparticles can release ArBu in the tumor microenvironment for chemtherapy, and ICG enables photothermal therapy under near-infrared laser irradiation. In vitro and in vivo mechanism studies revealed that the ZIAMH nanoplatform downregulated glucose metabolism related genes, resulting in the reduction of energy substances and metabolites in tumors. Additionally, it significantly promoted cell apoptosis by upregulating pro-apoptotic proteins such as Bax, Bax/Bcl-2, cytochrome C. Animal studies have shown that the tumor inhibition efficiency of ZIAMH nanomedicines was three fold higher than that of free drugs. Therefore, this study provides a new strategy for glucose metabolism-mediated bioenergetic therapy and PTT/CDT/CT combined therapy for tumors.
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Affiliation(s)
- Lihua Chen
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Jiaying Yang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Lingyu Jia
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xiaolu Wei
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Huijun Wang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Zhuo Liu
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing, 100191, China
| | - Shan Jiang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Pengyue Li
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Yanyan Zhou
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Hongjie Wang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Nan Si
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Baolin Bian
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Qinghe Zhao
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Haiyu Zhao
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
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22
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Alsaafeen BH, Ali BR, Elkord E. Resistance mechanisms to immune checkpoint inhibitors: updated insights. Mol Cancer 2025; 24:20. [PMID: 39815294 PMCID: PMC11734352 DOI: 10.1186/s12943-024-02212-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 12/25/2024] [Indexed: 01/18/2025] Open
Abstract
The last decade has witnessed unprecedented succusses with the use of immune checkpoint inhibitors in treating cancer. Nevertheless, the proportion of patients who respond favorably to the treatment remained rather modest, partially due to treatment resistance. This has fueled a wave of research into potential mechanisms of resistance to immune checkpoint inhibitors which can be classified into primary resistance or acquired resistance after an initial response. In the current review, we summarize what is known so far about the mechanisms of resistance in terms of being tumor-intrinsic or tumor-extrinsic taking into account the multimodal crosstalk between the tumor, immune system compartment and other host-related factors.
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Affiliation(s)
- Besan H Alsaafeen
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box: 15551, Al-Ain, United Arab Emirates
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Bassam R Ali
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box: 15551, Al-Ain, United Arab Emirates.
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain, United Arab Emirates.
| | - Eyad Elkord
- Department of Biosciences and Bioinformatics & Suzhou Municipal Key Lab of Biomedical Sciences and Translational Immunology, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China.
- College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates.
- Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, UK.
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23
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Yang L, Li S, Yu L, Leng J, Li N. Targeting glycolysis: exploring a new frontier in glioblastoma therapy. Front Immunol 2025; 15:1522392. [PMID: 39877360 PMCID: PMC11772265 DOI: 10.3389/fimmu.2024.1522392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Glioblastoma(GBM) is a highly malignant primary central nervous system tumor that poses a significant threat to patient survival due to its treatment resistance and rapid recurrence.Current treatment options, including maximal safe surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy, have limited efficacy.In recent years, the role of glycolytic metabolic reprogramming in GBM has garnered increasing attention. This review delves into the pivotal role of glycolytic metabolic reprogramming in GBM, with a particular focus on the multifaceted roles of lactate, a key metabolic product, within the tumor microenvironment (TME). Lactate has been implicated in promoting tumor cell proliferation, invasion, and immune evasion. Additionally, this review systematically analyzes potential therapeutic strategies targeting key molecules within the glycolytic pathway, such as Glucose Transporters (GLUTs), Monocarboxylate Transporters(MCTs), Hexokinase 2 (HK2), 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), Pyruvate Kinase Isozyme Type M2 (PKM2), and the Lactate Dehydrogenase A (LDHA). These studies provide a novel perspective for GBM treatment. Despite progress made in existing research, challenges remain, including drug penetration across the blood-brain barrier, side effects, and resistance. Future research will aim to address these challenges by improving drug delivery, minimizing side effects, and exploring combination therapies with radiotherapy, chemotherapy, and immunotherapy to develop more precise and effective personalized treatment strategies for GBM.
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Affiliation(s)
| | | | | | | | - Na Li
- Department of Oncology, Suining Central Hospital, Suining, Sichuan, China
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24
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Huang L, Zhao W, Sun L, Niu D, Zhu X, Jin C. Research progresses and hotspots on glucose metabolic reprogramming in breast cancer: a bibliometric analysis over the past two decades. Front Oncol 2025; 14:1493996. [PMID: 39876898 PMCID: PMC11772165 DOI: 10.3389/fonc.2024.1493996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 12/26/2024] [Indexed: 01/31/2025] Open
Abstract
Background Abnormal energy metabolism is a prominent characteristic of cancers. Increasing evidence has suggested the involvement of glucose metabolism reprogramming in the progression of breast cancer (BC). This article aims to provide a comprehensive overview of glucose metabolism reprogramming in BC through a bibliometric analysis. Methods Relevant literatures published from 2004 to 2024 were searched in the Web of Science Core Collection database, and a bibliometric analysis was conducted using VOSviewer, CiteSpace, and Bibliometrix. Results In total, 957 publications reporting glucose metabolism reprogramming in BC were included, showing an increasing trend in the annual publication outputs. China ranked first in publication outputs, and the United States of America (USA) had a dominant place in citation counts. The research achievements of Thomas Jefferson University in the USA were at the forefront and widely cited. Lisanti, Michael P., and Sotgia, Federica were the most productive authors. Keyword analysis suggested that the mechanisms of glucose metabolism reprogramming in BC and related therapeutic strategies were the research hotspots. Conclusion This study, for the first time, elucidated the progresses and hotspots of in the research on glucose metabolism reprogramming in BC, highlighting its potential role in treating BC. Considering that the glycolytic reprogramming of BC is a complex biological process, it is imperative for countries to enhance cooperation in the pursuit of effective antimetabolic therapies to overcome challenges in BC treatment.
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Affiliation(s)
| | | | | | | | | | - Chunhui Jin
- Department of Oncology, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, China
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25
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Xiao X, Long F, Yu S, Wu W, Nie D, Ren X, Li W, Wang X, Yu L, Wang P, Wang G. Col1A1 as a new decoder of clinical features and immune microenvironment in ovarian cancer. Front Immunol 2025; 15:1496090. [PMID: 39845977 PMCID: PMC11750837 DOI: 10.3389/fimmu.2024.1496090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/12/2024] [Indexed: 01/24/2025] Open
Abstract
Backgrounds Collagen type I alpha 1 chain (COL1A1) is a key protein encoding fibrillar collagen, playing a crucial role in the tumor microenvironment (TME) due to its complex functions and close association with tumor invasiveness. This has made COL1A1 a focal point in cancer biology research. However, studies investigating the relationship between COL1A1 expression levels and clinical characteristics of ovarian cancer (OC) remain limited. Methods This study integrated resources from publicly available online databases and immunohistochemistry (IHC) techniques to analyze and validate COL1A1 expression in OC tissues, and evaluated its potential association with clinical features in OC patients. The prognostic value of COL1A1 was assessed using Kaplan-Meier (KM) survival curve analysis. The TIMER and TISIDB databases to explore the potential relationship between COL1A1 expression and immune microenvironment in OC tissues. The LinkedOmics and INPUT2 databases were used to analyze differential gene expression in OC, This was followed by enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) annotations to identify and predict potential signaling pathways associated with COL1A1. Results Our study demonstrated that COL1A1 expression was significantly elevated in OC tissues compared to normal ovarian tissues. This elevated expression was closely associated with tumor metastasis, poor prognosis, and advanced pathological stages in OC patients. Moreover, COL1A1 expression showed a significant correlation with immune cell infiltration and the expression of immune-related genes within the TME.Further analyses revealed that COL1A1 and its co-expressed genes were primarily enriched in key signaling pathways involved in OC invasion, metastasis, and angiogenesis, indicating its potential role in driving OC progression. Conclusions Our study found that upregulation of COL1A1 expression is significantly associated with lymph node metastasis of OC and can affect the immune microenvironment. Based on this, COL1A1 could serve as a promising biomarker for OC prognosis and provide a new perspective for the development of potential immunotherapies for patients with OC.
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Affiliation(s)
- Xiao Xiao
- Department of Gynecology, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Fangyi Long
- Laboratory Medicine Center, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Shaolan Yu
- Laboratory Medicine Center, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Wengjuan Wu
- Department of Gynecology, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Dayan Nie
- Laboratory Medicine Center, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Xiaoyan Ren
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
| | - Wen Li
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
| | - Xujuan Wang
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
| | - Ling Yu
- Laboratory Medicine Center, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Pinghan Wang
- Laboratory Medicine Center, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Gang Wang
- Department of Gynecology, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, Sichuan, China
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26
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Clay R, Li K, Jin L. Metabolic Signaling in the Tumor Microenvironment. Cancers (Basel) 2025; 17:155. [PMID: 39796781 PMCID: PMC11719658 DOI: 10.3390/cancers17010155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/18/2024] [Accepted: 01/03/2025] [Indexed: 01/13/2025] Open
Abstract
Cancer cells must reprogram their metabolism to sustain rapid growth. This is accomplished in part by switching to aerobic glycolysis, uncoupling glucose from mitochondrial metabolism, and performing anaplerosis via alternative carbon sources to replenish intermediates of the tricarboxylic acid (TCA) cycle and sustain oxidative phosphorylation (OXPHOS). While this metabolic program produces adequate biosynthetic intermediates, reducing agents, ATP, and epigenetic remodeling cofactors necessary to sustain growth, it also produces large amounts of byproducts that can generate a hostile tumor microenvironment (TME) characterized by low pH, redox stress, and poor oxygenation. In recent years, the focus of cancer metabolic research has shifted from the regulation and utilization of cancer cell-intrinsic pathways to studying how the metabolic landscape of the tumor affects the anti-tumor immune response. Recent discoveries point to the role that secreted metabolites within the TME play in crosstalk between tumor cell types to promote tumorigenesis and hinder the anti-tumor immune response. In this review, we will explore how crosstalk between metabolites of cancer cells, immune cells, and stromal cells drives tumorigenesis and what effects the competition for resources and metabolic crosstalk has on immune cell function.
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Affiliation(s)
| | | | - Lingtao Jin
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (R.C.); (K.L.)
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27
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Jiang Z, Xiong N, Yan R, Li ST, Liu H, Mao Q, Sun Y, Shen S, Ye L, Gao P, Zhang P, Jia W, Zhang H. PDHX acetylation facilitates tumor progression by disrupting PDC assembly and activating lactylation-mediated gene expression. Protein Cell 2025; 16:49-63. [PMID: 39311688 DOI: 10.1093/procel/pwae052] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 08/29/2024] [Indexed: 01/07/2025] Open
Abstract
Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis. Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase (E1), leaving other post-translational modifications largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma, disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (E2), thereby disrupting PDC assembly to inhibit its activation. PDC disruption results in the conversion of most glucose to lactate, contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression, facilitating tumor progression. These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity, linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.
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Affiliation(s)
- Zetan Jiang
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
- The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Nanchi Xiong
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
- The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
- Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China
| | - Ronghui Yan
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
- The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Shi-Ting Li
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China
| | - Haiying Liu
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
- The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Qiankun Mao
- The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Yuchen Sun
- The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Shengqi Shen
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China
| | - Ling Ye
- The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Ping Gao
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China
| | - Pinggen Zhang
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
- The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Weidong Jia
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Huafeng Zhang
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
- The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China
- Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China
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Zhang R, Wang W, Li A, Wang H, Liu X, Fan F, Wang Y, Zhang H, Chang J, Zhang Y, Wang H, Miao L, Huang B, Yang L, Zhang Y. β-receptor blocker enhances anti-tumor immunity via inhibiting lactate-induced norepinephrine metabolism of macrophages during malignant pleural effusion. Front Immunol 2025; 15:1497468. [PMID: 39830505 PMCID: PMC11739086 DOI: 10.3389/fimmu.2024.1497468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/05/2024] [Indexed: 01/22/2025] Open
Abstract
Introduction Malignant pleural effusion (MPE) is associated with poor quality of life and mortality in patients with tumors. In clinical practice, we observed that patients with malignant pleural effusion (MPE) and concurrent heart disease exhibited a decrease in MPE volumes following treatment with β-receptor blockers for heart disease. Immunosuppressive tumor microenvironment was found to play a substantial role in the progression of MPE, and mainly attributed to tumor-associated macrophages (TAMs). However, whether β-receptor blockers improve MPE through affecting the immune microenvironment especially TAMs and the potential mechanism behind remains unclear. Methods In this study, we collected the MPE samples from MPE and heart disease patients treated with propranolol, and performed flow cytometry experiment to evaluate the effect of propranolol on MPE immune microenvironment. Then, the mechanism that how propranolol effectively reprogrammed the immunosuppressive microenvironment of MPE was conducted by the experiments of mass spectrometry, RNA-seq, flow cytometry, immunofluorescence, western blotting, etc. Lastly, to further evaluate the effect of propranolol on MPE therapy in vivo, we developed a mouse model of MPE. We administrated propranolol into MPE-bearing mice to investigate the therapy efficacy and the changes of MPE microenvironment by the experiments of computed tomography (CT) scanning, flow cytometry, etc. Results We observed that propranolol treatment in MPE patients with heart disease decreased TAM frequency and immunosuppression and enhanced anti-tumor immunity. Macrophages in MPE exhibited an immunosuppressive phenotype via the activation of norepinephrine metabolism. Subsequently, we found that lactate was increased in MPE and may contribute to an increase in TAM frequency and inhibition of anti-tumor immunity by macrophages. Additionally, lactate triggered phenylalanine/norepinephrine signaling and further induced macrophage immunosuppression in an ERK-depended way. Lastly, in the MPE mouse model, propranolol inhibited MPE development and reversed the immune microenvironment of MPE. Discussion Here, we reveal the mechanism by which lactate induces macrophage immunosuppression via activating phenylalanine/norepinephrine signaling. Our findings highlight that blocking norepinephrine signaling by β-receptor blockers is an attractive therapeutic strategy to enhance anti-tumor immunity in the context of MPE.
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Affiliation(s)
- Ru Zhang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Weijia Wang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Aitian Li
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Huishang Wang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaoyan Liu
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Feifei Fan
- Respiratory Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ying Wang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Huanyu Zhang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jingxia Chang
- Respiratory Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yinyin Zhang
- Hematology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hongmin Wang
- Respiratory Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lijun Miao
- Respiratory Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Bo Huang
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China
| | - Li Yang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Yi Zhang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- School of Public Health, Zhengzhou University, Zhengzhou, Henan, China
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Muto S, Ozaki Y, Yamaguchi H, Watanabe M, Okabe N, Matsumura Y, Hamada K, Suzuki H. Tumor β-Catenin Expression Associated With Poor Prognosis to Anti-PD-1 Antibody Monotherapy in Non-small Cell Lung Cancer. CANCER DIAGNOSIS & PROGNOSIS 2025; 5:32-41. [PMID: 39758230 PMCID: PMC11696345 DOI: 10.21873/cdp.10409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/20/2024] [Accepted: 11/21/2024] [Indexed: 01/07/2025]
Abstract
Background/Aim Tumor intrinsic β-catenin signaling has been reported to influence the tumor immune microenvironment and may be a resistance mechanism to immune checkpoint inhibitors in various cancers. Patients and Methods We studied the association between tumor β-catenin expression and survival in 50 patients with non-small cell lung cancer (NSCLC) treated with anti-programmed death-1 antibody monotherapy. Tumor β-catenin expression was evaluated by immunohistochemistry. Results Patients with positive tumor β-catenin expression (20% of all patients) had worse progression-free survival and overall survival compared with those with negative tumor β-catenin expression. Patients with positive tumor β-catenin expression had reduced CD8+ cell and CD11c+ cell infiltration into tumor nests than those with negative tumor β-catenin expression. RT-PCR of tumor tissue revealed that patients with positive tumor β-catenin expression showed lower gene expression of CD8A, CD4, IFN-γ, BATF3, and CCL4. Knockdown of CTNNB1 tended to increase CCL4 expression, likely mediated by ATF3, in a lung cancer cell line with positive β-catenin expression. Conclusion NSCLC patients with positive tumor β-catenin expression that were treated with anti-programmed death-1 antibody monotherapy had poor prognosis.
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Affiliation(s)
- Satoshi Muto
- Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan
| | - Yuki Ozaki
- Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan
| | - Hikaru Yamaguchi
- Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan
| | - Masayuki Watanabe
- Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan
| | - Naoyuki Okabe
- Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan
| | - Yuki Matsumura
- Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan
| | - Kazuyuki Hamada
- Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan
| | - Hiroyuki Suzuki
- Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan
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Wu H, Chen S, Li X, Li Y, Shi H, Qing Y, Shi B, Tang Y, Yan Z, Hao Y, Wang D, Liu W. RNA modifications in cancer. MedComm (Beijing) 2025; 6:e70042. [PMID: 39802639 PMCID: PMC11718328 DOI: 10.1002/mco2.70042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 11/12/2024] [Accepted: 11/14/2024] [Indexed: 01/16/2025] Open
Abstract
RNA modifications are emerging as critical cancer regulators that influence tumorigenesis and progression. Key modifications, such as N6-methyladenosine (m6A) and 5-methylcytosine (m5C), are implicated in various cellular processes. These modifications are regulated by proteins that write, erase, and read RNA and modulate RNA stability, splicing, translation, and degradation. Recent studies have highlighted their roles in metabolic reprogramming, signaling pathways, and cell cycle control, which are essential for tumor proliferation and survival. Despite these scientific advances, the precise mechanisms by which RNA modifications affect cancer remain inadequately understood. This review comprehensively examines the role RNA modifications play in cancer proliferation, metastasis, and programmed cell death, including apoptosis, autophagy, and ferroptosis. It explores their effects on epithelial-mesenchymal transition (EMT) and the immune microenvironment, particularly in cancer metastasis. Furthermore, RNA modifications' potential in cancer therapies, including conventional treatments, immunotherapy, and targeted therapies, is discussed. By addressing these aspects, this review aims to bridge current research gaps and underscore the therapeutic potential of targeting RNA modifications to improve cancer treatment strategies and patient outcomes.
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Affiliation(s)
- Han Wu
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Shi Chen
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Xiang Li
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Yuyang Li
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - He Shi
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Yiwen Qing
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
| | - Bohe Shi
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Yifei Tang
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Zhuoyi Yan
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Yang Hao
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Dongxu Wang
- Laboratory Animal CenterCollege of Animal ScienceJilin University, ChangchunJilin provinceChina
| | - Weiwei Liu
- Department of Oral and Maxillofacial SurgeryHospital of StomatologyJilin University, ChangchunJilin provinceChina
- Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingHospital of StomatologyJilin University, ChangchunJilin provincleChina
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Wu Y, Jiang X, Yu Z, Xing Z, Ma Y, Qing H. Mechanisms of Anti-PD Therapy Resistance in Digestive System Neoplasms. Recent Pat Anticancer Drug Discov 2025; 20:1-25. [PMID: 38305306 DOI: 10.2174/0115748928269276231120103256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 09/25/2023] [Accepted: 10/03/2023] [Indexed: 02/03/2024]
Abstract
Digestive system neoplasms are highly heterogeneous and exhibit complex resistance mechanisms that render anti-programmed cell death protein (PD) therapies poorly effective. The tumor microenvironment (TME) plays a pivotal role in tumor development, apart from supplying energy for tumor proliferation and impeding the body's anti-tumor immune response, the TME actively facilitates tumor progression and immune escape via diverse pathways, which include the modulation of heritable gene expression alterations and the intricate interplay with the gut microbiota. In this review, we aim to elucidate the mechanisms underlying drug resistance in digestive tumors, focusing on immune-mediated resistance, microbial crosstalk, metabolism, and epigenetics. We will highlight the unique characteristics of each digestive tumor and emphasize the significance of the tumor immune microenvironment (TIME). Furthermore, we will discuss the current therapeutic strategies that hold promise for combination with cancer immune normalization therapies. This review aims to provide a thorough understanding of the resistance mechanisms in digestive tumors and offer insights into potential therapeutic interventions.
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Affiliation(s)
- Yuxia Wu
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Xiangyan Jiang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Zeyuan Yu
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Zongrui Xing
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yong Ma
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Huiguo Qing
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
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Wang Q, Jin L, Yang H, Yu L, Cao X, Mao Z. Bacteria/Nanozyme Composites: New Therapeutics for Disease Treatment. SMALL METHODS 2025; 9:e2400610. [PMID: 38923867 DOI: 10.1002/smtd.202400610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 06/11/2024] [Indexed: 06/28/2024]
Abstract
Bacterial therapy is recognized as a cost-effective treatment for several diseases. However, its development is hindered by limited functionality, weak inherent therapeutic effects, and vulnerability to harsh microenvironmental conditions, leading to suboptimal treatment activity. Enhancing bacterial activity and therapeutic outcomes emerges as a pivotal challenge. Nanozymes have garnered significant attention due to their enzyme-mimic activities and high stability. They enable bacteria to mimic the functions of gene-edited bacteria expressing the same functional enzymes, thereby improving bacterial activity and therapeutic efficacy. This review delineates the therapeutic mechanisms of bacteria and nanozymes, followed by a summary of strategies for preparing bacteria/nanozyme composites. Additionally, the synergistic effects of such composites in biomedical applications such as gastrointestinal diseases and tumors are highlighted. Finally, the challenges of bacteria/nanozyme composites are discussed and propose potential solutions. This study aims to provide valuable insights to offer theoretical guidance for the advancement of nanomaterial-assisted bacterial therapy.
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Affiliation(s)
- Qirui Wang
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Lulu Jin
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Huang Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Lisha Yu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Xinran Cao
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Zhengwei Mao
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
- State Key Laboratory of Transvascular Implantation Devices, Zhejiang, Hangzhou, 310009, China
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Yao J, Ji L, Wang G, Ding J. Effect of neutrophils on tumor immunity and immunotherapy resistance with underlying mechanisms. Cancer Commun (Lond) 2025; 45:15-42. [PMID: 39485719 PMCID: PMC11758154 DOI: 10.1002/cac2.12613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 09/08/2024] [Accepted: 09/17/2024] [Indexed: 11/03/2024] Open
Abstract
Neutrophils are key mediators of the immune response and play essential roles in the development of tumors and immune evasion. Emerging studies indicate that neutrophils also play a critical role in the immunotherapy resistance in cancer. In this review, firstly, we summarize the novel classification and phenotypes of neutrophils and describe the regulatory relationships between neutrophils and tumor metabolism, flora microecology, neuroendocrine and tumor therapy from a new perspective. Secondly, we review the mechanisms by which neutrophils affect drug resistance in tumor immunotherapy from the aspects of the immune microenvironment, tumor antigens, and epigenetics. Finally, we propose several promising strategies for overcoming tumor immunotherapy resistance by targeting neutrophils and provide new research ideas in this area.
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Affiliation(s)
- Jiali Yao
- Clinical Cancer InstituteCenter for Translational MedicineNaval Medical UniversityShanghaiChina
| | - Linlin Ji
- Clinical Cancer InstituteCenter for Translational MedicineNaval Medical UniversityShanghaiChina
| | - Guang Wang
- Clinical Cancer InstituteCenter for Translational MedicineNaval Medical UniversityShanghaiChina
| | - Jin Ding
- Clinical Cancer InstituteCenter for Translational MedicineNaval Medical UniversityShanghaiChina
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Wang M, Guo X, Liu X, Huang L, Yang C. Artificial Intelligence-Guided Identification of IGFBP7 as a Critical Indicator in Lactic Metabolism Determines Immunotherapy Response in Stomach Adenocarcinoma. J Cell Mol Med 2025; 29:e70301. [PMID: 39788916 PMCID: PMC11717556 DOI: 10.1111/jcmm.70301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 11/28/2024] [Accepted: 12/10/2024] [Indexed: 01/12/2025] Open
Abstract
Due to considerable tumour heterogeneity, stomach adenocarcinoma (STAD) has a poor prognosis and varies in response to treatment, making it one of the main causes of cancer-related mortality globally. Recent data point to a significant role for metabolic reprogramming, namely dysregulated lactic acid metabolism, in the evolution of STAD and treatment resistance. This study used a series of artificial intelligence-related approaches to identify IGFBP7, a Schlafen family member, as a critical factor in determining the response to immunotherapy and lactic acid metabolism in STAD patients. Computational analyses revealed that a high lactic metabolism (LM) state was associated with poor survival in STAD patients. Further biological network-based investigations identified a key subnetwork closely linked to LM. Machine learning techniques, such as random forest and least absolute shrinkage and selection operator, highlighted IGFBP7 as a crucial indicator in STAD. Functional annotations showed that IGFBP7 expression was linked to important immune and inflammatory pathways. In vitro experiments demonstrated that silencing IGFBP7 suppressed cell proliferation and migration. Furthermore, heightened susceptibility to several chemotherapeutic drugs was linked to elevated IGFBP7 levels. In conclusion, this work sheds light on the mechanisms by which the lactate metabolism-related indicator IGFBP7 affects the tumour immune milieu and the response to immunotherapy in STAD. The results point to IGFBP7 as a possible therapeutic target and predictive biomarker for the treatment of STAD.
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Affiliation(s)
- Minghua Wang
- Department of General SurgeryThe Second Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina
| | - Xiaofei Guo
- Department of OncologyThe 962 Hospital of the Chinese People's Liberation Army Joint Logistic Support ForceHarbinHeilongjiangChina
| | - Xuyun Liu
- Department of General SurgeryThe Second Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina
| | - Lei Huang
- Department of General SurgeryThe Second Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina
| | - Chuang Yang
- Department of General SurgeryThe Second Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina
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Koganemaru S, Koyama S, Suto F, Koga M, Inaki K, Kuwahara Y, Arita T, Hirata T, Goto H, Wada N, Kobayashi M, Shibutani T, Okabayashi T, Nakamaru K, Kawazoe A, Togashi Y, Nishikawa H, Shitara K. The Tumor Immune Microenvironment and Therapeutic Efficacy of Trastuzumab Deruxtecan in Gastric Cancer. CANCER RESEARCH COMMUNICATIONS 2025; 5:84-93. [PMID: 39679910 PMCID: PMC11729160 DOI: 10.1158/2767-9764.crc-24-0302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 08/01/2024] [Accepted: 12/11/2024] [Indexed: 12/17/2024]
Abstract
SIGNIFICANCE This biomarker study explored HER2 expression levels and immune cell characteristics that may affect response to T-DXd using tumor tissue samples collected from clinical trial participants. The results suggest that HER2 expression levels and tumor characteristics before the initiation of T-DXd may correlate with the efficacy of the drug.
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Affiliation(s)
- Shigehiro Koganemaru
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shohei Koyama
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Chiba, Japan
- Department of Immunogenomic Medicine, Research Institute, National Cancer Center, Tokyo, Japan
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Fumitaka Suto
- Translational Science Department, Precision Medicine Function, Daiichi Sankyo, Inc., Basking Ridge, New Jersey
| | - Makito Koga
- Translational Science Department I, Precision Medicine Function, Daiichi Sankyo, Co., Ltd., Tokyo, Japan
| | - Koichiro Inaki
- Oncology Medical Science Department, Medical Affairs Division, Daiichi Sankyo, Co., Ltd., Tokyo, Japan
| | - Yusuke Kuwahara
- Translational Science Department, Precision Medicine Function, Daiichi Sankyo, Inc., Basking Ridge, New Jersey
| | - Takeo Arita
- Translational Science Department I, Precision Medicine Function, Daiichi Sankyo, Co., Ltd., Tokyo, Japan
| | - Tsuyoshi Hirata
- Translational Science Department, Precision Medicine Function, Daiichi Sankyo, Inc., Basking Ridge, New Jersey
| | - Hiroki Goto
- Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan
| | - Naoya Wada
- Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan
| | - Maki Kobayashi
- Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan
| | - Tomoko Shibutani
- Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan
| | - Tatsuya Okabayashi
- Clinical Development Department I, Development Function, Daiichi Sankyo, Co., Ltd., Tokyo, Japan
| | - Kenji Nakamaru
- Translational Science Department I, Precision Medicine Function, Daiichi Sankyo, Co., Ltd., Tokyo, Japan
| | - Akihito Kawazoe
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yousuke Togashi
- Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Chiba, Japan
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kohei Shitara
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Liu X, Xu D, Zhou C, Zhong Y, Geng H, Huang C, Shen Y, Xia X, Wang C, Zhu C, Cao H. Association of PD-1 + Treg/PD-1 + CD8 ratio and tertiary lymphoid structures with prognosis and response in advanced gastric cancer patients receiving preoperative treatment. J Transl Med 2024; 22:1152. [PMID: 39731106 DOI: 10.1186/s12967-024-05867-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 11/08/2024] [Indexed: 12/29/2024] Open
Abstract
BACKGROUND Recent studies have highlighted the distinct ratio of PD-1 + Treg/PD-1 + CD8 for prognosis prediction. However, it remains unclear about the association of this ratio and tertiary lymphoid structures (TLS) with prognosis and response to neoadjuvant or conversion therapy in advanced gastric cancer. METHODS Firstly, fresh postoperative samples from 68 gastric cancer patients in Renji Hospital were collected. Meanwhile, immune cell infiltration as well as clinical prognosis analysis were conducted. Subsequently, we further systematically evaluated flow cytometry analysis of tumor samples and TLS expression in 38 gastric cancer patients with different response situations after neoadjuvant therapy. Also, a Renji conversion therapy cohort including 10 patients with complete matching samples before and after treatment was established to receive RNA sequencing analysis and multiplex immunohistochemistry (mIHC) tests. The corresponding TLS score and immune cell infiltration were further compared based on therapeutic response variations. RESULTS In general, the ratio of PD-1 + Treg/PD-1 + CD8>1 could be regarded as an independent predictor of prognosis in advanced gastric cancer patients. Moreover, PD-1 + Treg/PD-1 + CD8 < 1 and high expression of TLS could indicate better neoadjuvant therapy response and extended survival time in advanved gastric cancer patients. Besides, PD-1 + Treg/PD-1 + CD8 low &TLS high group could predict better progression free survival time (PFS) in complete response (CR) subgroup. In response group after conversion therapy, the number of PD-1 + CD8 + T cells significantly increased, mainly occurring outside the TLSs. Meanwhile, the TLSs were also considerably activated as we could observed. CONCLUSIONS This study underlined that combining PD-1 + Treg/PD-1 + CD8 ratio and TLS were significantly associated with prognosis and preoperative treatment response in advanced gastric cancer. Inspiringly, these indicators have the potential to elucidate the immune balance of advanced gastric cancer patients and can accurately guide subsequent therapeutic strategies.
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Affiliation(s)
- Xu Liu
- Department of Gastrointestinal Surgery, School of Medicine, RenJi Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Pudong New Area, Shanghai, 200025, China
| | - Danhua Xu
- Department of Gastrointestinal Surgery, School of Medicine, RenJi Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Pudong New Area, Shanghai, 200025, China
| | - Chengbei Zhou
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200025, China
| | - Yiqing Zhong
- Department of Gastrointestinal Surgery, School of Medicine, RenJi Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Pudong New Area, Shanghai, 200025, China
| | - Haigang Geng
- Department of Gastrointestinal Surgery, School of Medicine, RenJi Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Pudong New Area, Shanghai, 200025, China
| | - Chen Huang
- Department of Gastrointestinal Surgery, School of Medicine, RenJi Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Pudong New Area, Shanghai, 200025, China
| | - Yanying Shen
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200025, China
| | - Xiang Xia
- Department of Gastrointestinal Surgery, School of Medicine, RenJi Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Pudong New Area, Shanghai, 200025, China
| | - Chaojie Wang
- Department of Gastrointestinal Surgery, School of Medicine, RenJi Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Pudong New Area, Shanghai, 200025, China
| | - Chunchao Zhu
- Department of Gastrointestinal Surgery, School of Medicine, RenJi Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Pudong New Area, Shanghai, 200025, China.
| | - Hui Cao
- Department of Gastrointestinal Surgery, School of Medicine, RenJi Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Pudong New Area, Shanghai, 200025, China.
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Griffin KV, Saunders MN, Lyssiotis CA, Shea LD. Engineering immunity using metabolically active polymeric nanoparticles. Trends Biotechnol 2024:S0167-7799(24)00345-7. [PMID: 39732608 DOI: 10.1016/j.tibtech.2024.11.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 12/30/2024]
Abstract
Immune system functions play crucial roles in both health and disease, and these functions are regulated by their metabolic programming. The field of immune engineering has emerged to develop therapeutic strategies, including polymeric nanoparticles (NPs), that can direct immune cell phenotype and function by directing immunometabolic changes. Precise control of bioenergetic processes may offer the opportunity to prevent undesired immune activity and improve disease-specific outcomes. In this review we discuss the role that polymeric NPs can play in shaping immunometabolism and subsequent immune system activity through particle-mediated delivery of metabolically active agents as either structural components or cargo.
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Affiliation(s)
- Kate V Griffin
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Michael N Saunders
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Costas A Lyssiotis
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
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38
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Xue Q, Peng W, Zhang S, Wei X, Ye L, Wang Z, Xiang X, Liu Y, Wang H, Zhou Q. Lactylation-driven TNFR2 expression in regulatory T cells promotes the progression of malignant pleural effusion. J Immunother Cancer 2024; 12:e010040. [PMID: 39721754 PMCID: PMC11683941 DOI: 10.1136/jitc-2024-010040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 11/06/2024] [Indexed: 12/28/2024] Open
Abstract
BACKGROUND Although tumor necrosis factor receptor 2 (TNFR2) has been recognized as an attractive next-generation candidate target for cancer immunotherapy, the factors that regulate the gene expression and their mechanistic effects on tumor-infiltrating regulatory T cells (Treg cells) remain poorly understood. METHODS Single-cell RNA sequencing analysis was employed to analyze the phenotypic and functional differences between TNFR2+ Treg cells and TNFR2- Treg cells. Malignant pleural effusion (MPE) from humans and mouse was used to investigate the potential mechanisms by which lactate regulates TNFR2 expression. RESULTS Treg cells with high TNFR2 expression exhibited elevated levels of immune checkpoint molecules. Additionally, the high expression of TNFR2 on Treg cells was positively correlated with a poor prognosis in MPE patients. Moreover, we revealed that lactate upregulated TNFR2 expression on Treg cells, thereby enhancing their immunosuppressive function in MPE. Mechanistically, lactate modulated the gene transcription of transcription factor nuclear factor-κB p65 (NF-κB p65) through histone H3K18 lactylation (H3K18la), subsequently upregulating the gene expression of TNFR2 and expediting the progression of MPE. Notably, lactate metabolism blockade combined with immune checkpoint blockade (ICB) therapy effectively enhanced the efficacy of ICB therapy, prolonged the survival time of MPE mice, and improved immunosuppression in the microenvironment of MPE. CONCLUSIONS The study explains the mechanism that regulates TNFR2 expression on Treg cells and its function in MPE progression, providing novel insights into the epigenetic regulation of tumor development and metabolic strategies for MPE treatment by targeting lactate metabolism in Treg cells.
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Affiliation(s)
- Qianqian Xue
- Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China
| | - Wenbei Peng
- Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China
| | - Siyu Zhang
- Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoshan Wei
- Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China
| | - Linlin Ye
- Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China
| | - Zihao Wang
- Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China
| | - Xuan Xiang
- Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China
| | - Yao Liu
- Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China
| | - Haolei Wang
- Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China
| | - Qiong Zhou
- Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China
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Hao ZN, Tan XP, Zhang Q, Li J, Xia R, Ma Z. Lactate and Lactylation: Dual Regulators of T-Cell-Mediated Tumor Immunity and Immunotherapy. Biomolecules 2024; 14:1646. [PMID: 39766353 PMCID: PMC11674224 DOI: 10.3390/biom14121646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/14/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly in T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of the Warburg effect, contribute to immune suppression through CD8+ T cell functionality and by promoting regulatory T cell (Treg) activity. Lactylation, a post-translational modification (PTM), alters histone and non-histone proteins, influencing gene expression and further reinforcing immune suppression. In the complex TME, lactate and its derivative, lactylation, are not only associated with immune suppression but can also, under certain conditions, exert immunostimulatory effects that enhance cytotoxic responses. This review describes the dual roles of lactate and lactylation in T-cell-mediated tumor immunity, analyzing how these factors contribute to immune evasion, therapeutic resistance, and immune activation. Furthermore, the article highlights emerging therapeutic strategies aimed at inhibiting lactate production or disrupting lactylation pathways to achieve a balanced regulation of these dual effects. These strategies offer new insights into overcoming tumor-induced immune suppression and hold the potential to improve the efficacy of cancer immunotherapies.
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Affiliation(s)
- Zhi-Nan Hao
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Xiao-Ping Tan
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
- The Third Clinical Medical College of Yangtze University, Jingzhou Hospital of Traditional Chinese Medicine, Jingzhou 434023, China
| | - Qing Zhang
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Jie Li
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Ruohan Xia
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
| | - Zhaowu Ma
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
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Huang T, Li F, Wang Y, Gu J, Lu L. Tumor-infiltrating regulatory T cell: A promising therapeutic target in tumor microenvironment. Chin Med J (Engl) 2024; 137:2996-3009. [PMID: 39679474 PMCID: PMC11706582 DOI: 10.1097/cm9.0000000000003450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Indexed: 12/17/2024] Open
Abstract
ABSTRACT Regulatory T cell (Tregs) predominantly maintain the immune balance and prevent autoimmunity via their immunosuppressive functions. However, tumor-infiltrating Tregs (TI-Tregs) may mediate tumor immune tolerance in complex tumor microenvironments, resulting in poor prognosis. Distinguishing specific TI-Treg subpopulations from peripheral Tregs and intratumoral conventional T cells (Tconvs) has recently emerged as an important topic in antitumor therapy. In this review, we summarize novel therapeutic approaches targeting both the metabolic pathways and hallmarks of TI-Tregs in preclinical and clinical studies. Although the phenotypic and functional diversity of TI-Tregs remains unclear, our review provides new insights into TI-Treg-based therapies and facilitates precision medicine for tumor treatment.
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Affiliation(s)
- Tianning Huang
- Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210029, China
| | - Fan Li
- Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210029, China
| | - Yiming Wang
- Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210029, China
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jian Gu
- Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210029, China
| | - Ling Lu
- Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210029, China
- Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221011, China
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41
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Feng B, Li R, Li W, Tang L. Metabolic immunoengineering approaches to enhance CD8 + T cell-based cancer immunotherapy. Cell Syst 2024; 15:1225-1244. [PMID: 39701038 DOI: 10.1016/j.cels.2024.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/24/2024] [Accepted: 11/14/2024] [Indexed: 12/21/2024]
Abstract
Many cancer immunotherapies rely on robust CD8+ T cells capable of eliminating cancer cells and establishing long-term tumor control. Recent insights into immunometabolism highlight the importance of nutrients and metabolites in T cell activation and differentiation. Within the tumor microenvironment (TME), CD8+ tumor-infiltrating lymphocytes (TILs) undergo metabolic adaptations to survive but compromise their effector function and differentiation. Targeting metabolism holds promise for enhancing CD8+ T cell-mediated antitumor immunity. Here, we overview the metabolic features of CD8+ TILs and their impact on T cell effector function and differentiation. We also highlight immunoengineering strategies by leveraging the Yin-Yang of metabolic modulation for improving cancer immunotherapy.
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Affiliation(s)
- Bing Feng
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Institute of Materials Science & Engineering, EPFL, 1015 Lausanne, Switzerland
| | - Rongrong Li
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
| | - Weilin Li
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
| | - Li Tang
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Institute of Materials Science & Engineering, EPFL, 1015 Lausanne, Switzerland.
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Liu Z, Dai B, Bao J, Pan Y. T cell metabolism in kidney immune homeostasis. Front Immunol 2024; 15:1498808. [PMID: 39737193 PMCID: PMC11684269 DOI: 10.3389/fimmu.2024.1498808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 11/27/2024] [Indexed: 01/01/2025] Open
Abstract
Kidney immune homeostasis is intricately linked to T cells. Inappropriate differentiation, activation, and effector functions of T cells lead to a spectrum of kidney disease. While executing immune functions, T cells undergo a series of metabolic rewiring to meet the rapid energy demand. The key enzymes and metabolites involved in T cell metabolism metabolically and epigenetically modulate T cells' differentiation, activation, and effector functions, thereby being capable of modulating kidney immune homeostasis. In this review, we first summarize the latest advancements in T cell immunometabolism. Second, we outline the alterations in the renal microenvironment under certain kidney disease conditions. Ultimately, we highlight the metabolic modulation of T cells within kidney immune homeostasis, which may shed light on new strategies for treating kidney disease.
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Affiliation(s)
- Zikang Liu
- Department of Nephrology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Binbin Dai
- Department of Nephrology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Jiwen Bao
- Department of Nephrology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Yangbin Pan
- Department of Nephrology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
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Aokage K, Koyama S, Kumagai S, Nomura K, Shimada Y, Yoh K, Wakabayashi M, Fukutani M, Furuya H, Miyoshi T, Tane K, Samejima J, Taki T, Hayashi T, Matsubayashi J, Ishii G, Nishikawa H, Ikeda N, Tsuboi M. Efficacy, Safety, and Influence on the Tumor Microenvironment of Neoadjuvant Pembrolizumab plus Ramucirumab for PD-L1-Positive NSCLC: A Phase II Trial (EAST ENERGY). Clin Cancer Res 2024; 30:5584-5592. [PMID: 39453771 DOI: 10.1158/1078-0432.ccr-24-1561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/19/2024] [Accepted: 10/23/2024] [Indexed: 10/27/2024]
Abstract
PURPOSE Angiogenesis inhibitors are known to modify tumor immunity. Combination of angiogenesis inhibitors with immune checkpoint inhibitors has shown efficacy against many types of cancers, including non-small cell lung cancer (NSCLC). We investigated the feasibility of neoadjuvant therapy with pembrolizumab and ramucirumab, a VEGFR-2 antagonist for patients with PD-L1-positive NSCLC, and its influence on the tumor microenvironment. PATIENTS AND METHODS Patients with pathologically proven, PD-L1-positive, clinical stage IB to IIIA NSCLC were eligible. Patients received two cycles of pembrolizumab (200 mg/body) and ramucirumab (10 mg/kg) every 3 weeks. Surgery was scheduled 4 to 8 weeks after the last dose. The primary endpoint was the major pathologic response rate by a blinded independent pathologic review. The sample size was 24 patients. Exploratory endpoints were evaluated to elucidate the effects of neoadjuvant therapy on the tumor microenvironment. RESULTS The 24 eligible patients were enrolled between July 2019 and April 2022. The major pathologic response rate was 50.0% (90% confidence interval, 31.9%-68.1%). Six patients showed pathologic complete response. Grade 3 adverse events (AE) occurred in nine patients (37.5%), including three immune-related AEs (acute tubulointerstitial nephritis in two cases and polymyalgia rheumatica in one case). There were no grade 4 or 5 AEs. The transcriptome and multiplex IHC results suggested that tumors with greater CD8+ T-cell infiltration and higher expression of effector molecules at the baseline could show better sensitivity to treatment. CONCLUSIONS This new neoadjuvant combination of pembrolizumab plus ramucirumab was feasible, and anti-VEGF agents may enhance the effects of immune checkpoint inhibitors.
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Affiliation(s)
- Keiju Aokage
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shohei Koyama
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Shogo Kumagai
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Kotaro Nomura
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | | | - Kiyotaka Yoh
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masashi Wakabayashi
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Miki Fukutani
- Clinical Research Center, Hiroshima University Hospital, Hiroshima, Japan
| | - Hideki Furuya
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Tomohiro Miyoshi
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kenta Tane
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Joji Samejima
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Tetsuro Taki
- Development of Pathology and Clinical Laboratories, National Cancer Center, Kashiwa, Japan
| | - Takuo Hayashi
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Jun Matsubayashi
- Division of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan
| | - Genichiro Ishii
- Development of Pathology and Clinical Laboratories, National Cancer Center, Kashiwa, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Norihiko Ikeda
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| | - Masahiro Tsuboi
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
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Ren N, Zhang H, Li T, Ji H, Zhang Z, Wu H. ATP5J regulates microglial activation via mitochondrial dysfunction, exacerbating neuroinflammation in intracerebral hemorrhage. Front Immunol 2024; 15:1509370. [PMID: 39735538 PMCID: PMC11671693 DOI: 10.3389/fimmu.2024.1509370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/02/2024] [Indexed: 12/31/2024] Open
Abstract
Microglial-mediated neuroinflammation is crucial in the pathophysiological mechanisms of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). Mitochondria are central regulators of inflammation, influencing key pathways such as alternative splicing, and play a critical role in cell differentiation and function. Mitochondrial ATP synthase coupling factor 6 (ATP5J) participates in various pathological processes, such as cell proliferation, migration, and inflammation. However, the role of ATP5J in microglial activation and neuroinflammation post-ICH is poorly understood. This study aimed to investigate the effects of ATP5J on microglial activation and subsequent neuroinflammation in ICH and to elucidate the underlying mechanisms. We observed that ATP5J was upregulated in microglia after ICH. AAV9-mediated ATP5J overexpression worsened neurobehavioral deficits, disrupted the blood-brain barrier, and increased brain water content in ICH mice. Conversely, ATP5J knockdown ameliorated these effects. ATP5J overexpression also intensified microglial activation, neuronal apoptosis, and inflammatory responses in surrounding tissues post-ICH. ATP5J impaired microglial dynamics and reduced the proliferation and migration of microglia to injury sites. We used oxyhemoglobin (OxyHb) to stimulate BV2 cells and model ICH in vitro. Further in vitro studies showed that ATP5J overexpression enhanced OxyHb-induced microglial functional transformation. Mechanistically, ATP5J silencing reversed dynamin-related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1) upregulation in microglia post-OxyHb induction; reduced mitochondrial overdivision, excessive mitochondrial permeability transition pore opening, and reactive oxygen species production; restored normal mitochondrial ridge morphology; and partially restored mitochondrial respiratory electron transport chain activity. ATP5J silencing further alleviated OxyHb-induced mitochondrial dysfunction by regulating mitochondrial metabolism. Our results indicate that ATP5J is a key factor in regulating microglial functional transformation post-ICH by modulating mitochondrial dysfunction and metabolism, thereby positively regulate neuroinflammation. By inhibiting ATP5J, SBI following ICH could be prevented. Therefore, ATP5J could be a candidate for molecular and therapeutic target exploration to alleviate neuroinflammation post-ICH.
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Affiliation(s)
| | | | | | | | - Zhen Zhang
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China
| | - He Wu
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China
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Chen H, Lin Y, Chen J, Luo X, Kan Y, He Y, Zhu R, Jin J, Li D, Wang Y, Han Z. Targeting caspase-8: a new strategy for combating hepatocellular carcinoma. Front Immunol 2024; 15:1501659. [PMID: 39726605 PMCID: PMC11669555 DOI: 10.3389/fimmu.2024.1501659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/29/2024] [Indexed: 12/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents the most prevalent form of primary liver cancer and has a high mortality rate. Caspase-8 plays a pivotal role in an array of cellular signaling pathways and is essential for the governance of programmed cell death mechanisms, inflammatory responses, and the dynamics of the tumor microenvironment. Dysregulation of caspase-8 is intricately linked to the complex biological underpinnings of HCC. In this manuscript, we provide a comprehensive review of the regulatory roles of caspase-8 in apoptosis, necroptosis, pyroptosis, and PANoptosis, as well as its impact on inflammatory reactions and the intricate interplay with critical immune cells within the tumor microenvironment, such as tumor-associated macrophages, T cells, natural killer cells, and dendritic cells. Furthermore, we emphasize how caspase-8 plays pivotal roles in the development, progression, and drug resistance observed in HCC, and explore the potential of targeting caspase-8 as a promising strategy for HCC treatment.
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Affiliation(s)
- Haoran Chen
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Yumeng Lin
- Health Management Center, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jie Chen
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Xuemei Luo
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Yubo Kan
- Sichuan Provincial Woman’s and Children’s Hospital/The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, China
| | - Yuqi He
- Department of Blood Transfusion, Lu’an People’s Hospital, the Affiliated Hospital of Anhui Medical University, Lu’an, China
| | - Renhe Zhu
- Department of Blood Transfusion, Lu’an People’s Hospital, the Affiliated Hospital of Anhui Medical University, Lu’an, China
| | - Jiahui Jin
- Department of gastroenterology, Baoji Central Hospital, Baoji, China
| | - Dongxuan Li
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Yi Wang
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Zhongyu Han
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
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Viel S, Vivier E, Walzer T, Marçais A. Targeting metabolic dysfunction of CD8 T cells and natural killer cells in cancer. Nat Rev Drug Discov 2024:10.1038/s41573-024-01098-w. [PMID: 39668206 DOI: 10.1038/s41573-024-01098-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2024] [Indexed: 12/14/2024]
Abstract
The importance of metabolic pathways in regulating immune responses is now well established, and a mapping of the bioenergetic metabolism of different immune cell types is under way. CD8 T cells and natural killer (NK) cells contribute to cancer immunosurveillance through their cytotoxic functions and secretion of cytokines and chemokines, complementing each other in target recognition mechanisms. Several immunotherapies leverage these cell types by either stimulating their activity or redirecting their specificity against tumour cells. However, the anticancer activity of CD8 T cells and NK cells is rapidly diminished in the tumour microenvironment, closely linked to a decline in their metabolic capacities. Various strategies have been developed to restore cancer immunosurveillance, including targeting bioenergetic metabolism or genetic engineering. This Review provides an overview of metabolic dysfunction in CD8 T cells and NK cells within the tumour microenvironment, highlighting current therapies aiming to overcome these issues.
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Affiliation(s)
- Sébastien Viel
- Plateforme de Biothérapie et de Production de Médicaments de Thérapie Innovante, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Eric Vivier
- Innate Pharma Research Laboratories, Innate Pharma, Marseille, France
- Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
- APHM, Hôpital de la Timone, Marseille, France
- Paris Saclay Cancer Cluster, Villejuif, France
- Université Paris-Saclay, Gustave Roussy, Inserm, Prédicteurs moléculaires et nouvelles cibles en oncologie, Villejuif, France
| | - Thierry Walzer
- CIRI, Centre International de Recherche en Infectiologie, (Team Lyacts), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS UMR5308 ENS de Lyon, Lyon, France
| | - Antoine Marçais
- CIRI, Centre International de Recherche en Infectiologie, (Team Lyacts), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS UMR5308 ENS de Lyon, Lyon, France.
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Gao Y, Li A, Li Y, Guo H, He L, Li K, Shcharbin D, Shi X, Shen M. Dendrimer/Copper(II) Complex-Mediated siRNA Delivery Disrupts Lactate Metabolism to Reprogram the Local Immune Microenvironment against Tumor Growth and Metastasis. Biomacromolecules 2024; 25:7995-8005. [PMID: 39570391 DOI: 10.1021/acs.biomac.4c01249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2024]
Abstract
Solid tumors reprogram metabolic pathways to meet their biosynthesis demands, resulting in elevated levels of metabolites in the tumor microenvironment (TME), including lactate. Excessive accumulation and active transportation of lactate within the TME drives tumor progression, metastasis, and immunosuppression. Interruption of TME lactate metabolism is expected to restore antitumor responses and sensitize tumor immunotherapy. Herein, we developed phenylboronic acid- and pyridine-modified poly(amidoamine) dendrimer/copper(II) (Cu(II)) complexes, namely, D-Cu complexes, to deliver monocarboxylate transporter 4 siRNA (siMCT4) and disrupt the tumor lactate shuttle. The D-Cu complexes are shown to have a Cu(II)-mediated chemodynamic effect and T1-weighted magnetic resonance imaging potential (r1 relaxivity = 1.19 mM-1 s-1), enabling effective siMCT4 delivery to inhibit lactate efflux within cancer cells. In combination with a CD11b immune agonist, the treatment of D-Cu/siMCT4 polyplexes in a mouse breast tumor model alleviates local TME immunosuppression, leading to excellent inhibition of both primary tumor growth and lung metastasis.
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Affiliation(s)
- Yue Gao
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Aiyu Li
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Yanying Li
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Honghua Guo
- Department of Radiology, Shanghai Songjiang District Central Hospital, Shanghai 201600, China
| | - Liangyu He
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Kangan Li
- Department of Radiology, Shanghai Songjiang District Central Hospital, Shanghai 201600, China
| | - Dzmitry Shcharbin
- Institute of Biophysics and Cell Engineering of NASB, Akademicheskaja 27, 220072 Minsk, Belarus
| | - Xiangyang Shi
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Mingwu Shen
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
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Zhang R, Gao Y, Li C, Tao R, Mao G, Song T, Nie W, Liu S, Tao K, Li W. Hypoxia reconstructed colorectal tumor microenvironment weakening anti-tumor immunity: construction of a new prognosis predicting model through transcriptome analysis. Front Immunol 2024; 15:1425687. [PMID: 39712012 PMCID: PMC11659140 DOI: 10.3389/fimmu.2024.1425687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 11/18/2024] [Indexed: 12/24/2024] Open
Abstract
Background Hypoxia in the tumor microenvironment (TME) plays a pivotal role in the progression and prognosis of colorectal cancer (CRC). However, effective methods for assessing TME hypoxia remain lacking. This study aims to develop a novel hypoxia-related prognostic score (HPS) based on hypoxia-associated genes to improve CRC prognostication and inform treatment strategies. Methods Transcriptomic data from CRC patients were analyzed using Lasso regression to identify hypoxia-associated genes with the strongest prognostic significance. The identified genes were validated in vitro by assessing their expression under normoxic and hypoxic conditions in normal intestinal epithelial cells and CRC tumor cell lines. Functional relevance was explored through differential gene expression analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and protein-protein interaction (PPI) network construction. The association of HPS with extracellular matrix (ECM) composition, immune cell infiltration, and immune suppression was also investigated. Results Seven hypoxia-associated signature genes were identified, each demonstrating a strong correlation with CRC prognosis. The hypoxia-related prognostic score (HPS), derived from these genes, was significantly linked to changes in the TME. Specifically, HPS values were associated with alterations in ECM composition and distinct immune cell infiltration patterns. Higher HPS values corresponded to increased infiltration of immune-suppressive cells and reduced presence of anti-tumor immune cells. This imbalance promoted an immune-suppressive TME, facilitating tumor progression and immune evasion. Conclusions The hypoxia-related prognostic score (HPS) captures the regulatory influence of TME hypoxia on immune responses, offering valuable insights into its role in tumor progression. HPS holds promise as a prognostic tool and a guide for developing personalized treatment strategies in CRC.
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Affiliation(s)
- Ruizhi Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yisong Gao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chong Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruikang Tao
- Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA, United States
| | - Gan Mao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tianyu Song
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenxiang Nie
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Suao Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Tong H, Jiang Z, Song L, Tan K, Yin X, He C, Huang J, Li X, Jing X, Yun H, Li G, Zhao Y, Kang Q, Wei Y, Li R, Long Z, Yin J, Luo Q, Liang X, Wan Y, Zheng A, Lin N, Zhang T, Xu J, Yang X, Jiang Y, Li Y, Xiang Y, Zhang Y, Feng L, Lei Z, Shi H, Ma X. Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation. Cell Metab 2024; 36:2493-2510.e9. [PMID: 39577415 DOI: 10.1016/j.cmet.2024.10.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 07/29/2024] [Accepted: 10/21/2024] [Indexed: 11/24/2024]
Abstract
The effect of the serine/glycine-free diet (-SG diet) on colorectal cancer (CRC) remains unclear; meanwhile, programmed death-1 (PD-1) inhibitors are less effective for most CRC patients. Here, we demonstrate that the -SG diet inhibits CRC growth and promotes the accumulation of cytotoxic T cells to enhance antitumor immunity. Additionally, we also identified the lactylation of programmed death-ligand 1 (PD-L1) in tumor cells as a mechanism of immune evasion during cytotoxic T cell-mediated antitumor responses, and blocking the PD-1/PD-L1 signaling pathway is able to rejuvenate the function of CD8+ T cells recruited by the -SG diet, indicating the potential of combining the -SG diet with immunotherapy. We conducted a single-arm, phase I study (ChiCTR2300067929). The primary outcome suggests that the -SG diet is feasible and safe for regulating systemic immunity. Secondary outcomes include patient tolerability and potential antitumor effects. Collectively, our findings highlight the promising therapeutic potential of the -SG diet for treating solid tumors.
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Affiliation(s)
- Huan Tong
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zedong Jiang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Linlin Song
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China; Department of Ultrasound & Laboratory of Ultrasound Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Keqin Tan
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaomeng Yin
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | | | - Juan Huang
- Department of Hematology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Xiaoyue Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Wupai Technology Limited Liability Company, Chengdu, Sichuan, China
| | - Xiaofan Jing
- Department of Nutrition, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hong Yun
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Guangqi Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yunuo Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qianlong Kang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuhao Wei
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Renwei Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhiwen Long
- Recovery Plus Clinic, New York, NY 10019, USA
| | - Jun Yin
- Recovery Plus Clinic, New York, NY 10019, USA
| | - Qiang Luo
- Department of Oncology, Xinjin District Hospital of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiao Liang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yanzhi Wan
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Aiping Zheng
- Division of Head & Neck Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Nan Lin
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tao Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jiayi Xu
- Core Facilities, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xinggang Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuting Jiang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yueyi Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yu Xiang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yu Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lusi Feng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhen Lei
- Recovery Plus Clinic, New York, NY 10019, USA.
| | - Hubing Shi
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China.
| | - Xuelei Ma
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Zhong M, Yu Z, Wu Q, Lu B, Sun P, Zhang X, Yang L, Wu H. PCDHGA10 as a potential prognostic biomarker and correlated with immune infiltration in gastric cancer. Front Immunol 2024; 15:1500478. [PMID: 39687617 PMCID: PMC11647002 DOI: 10.3389/fimmu.2024.1500478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/11/2024] [Indexed: 12/18/2024] Open
Abstract
Background Gastric cancer (GC) is one of the most common malignant tumors and is associated with poor prognosis. To improve the prognosis of GC patients, an effective immune-related prognostic biomarker is urgent. Here, we aim to explore the correlation between the expression of procalcitonin gamma subfamily A, 10 (PCDHGA10) and clinicopathological characteristics, especially its relation with tumor-infiltrating immune cells (TILs) in GC. Methods The differential mRNA expression of PCDHGA10 between GC tissues and normal gastric mucosa and prognostic potential were assessed from The Cancer Genome Atlas (TCGA). Then, based on tissue microarrays (TMAs) with multiplex immunohistochemistry (mIHC) from GC patients, we statistically assess the correlation between PCDHGA10 protein expression and the clinical profiles and prognosis of the patients. Additionally, with IHC and mIHC, we applied the machine-learning algorithms to evaluate the localization and expression levels of TILs and immune checkpoints in the tumor microenvironment. We analyzed the relationship between PCDHGA10 protein expression and TILs and immune checkpoints. Results Through the database and TMA analysis, the expression of PCDHGA10 was significantly higher in GC tissues compared with normal tissues. High PCDHGA10 expression independently predicted poor prognosis in GC. Additionally, elevated PCDHGA10 expression was positively associated with the number of CD8+ T cells, CD68+ macrophages, Foxp3+ T cells, and CD4+ T cells in GC tissues and the stromal region. Besides, the expression of PCDHGA10 was positively correlated with immune checkpoints, including CTLA-4, LAG3, and PD-L1. Conclusions PCDHGA10 might be a potential prognostic marker and an immunological therapeutic target for GC.
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Affiliation(s)
- Mingyang Zhong
- Department of General Surgery, Medical School of Nantong University, & Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Zhuoqun Yu
- Department of General Surgery, Medical School of Nantong University, & Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Qianqian Wu
- Clinical and Translational Research Center & Institute of Oncology, Affiliated Hospital of Nantong University, Department of Oncology, Medical School of Nantong University, Nantong, Jiangsu, China
| | - Bing Lu
- Clinical and Translational Research Center & Institute of Oncology, Affiliated Hospital of Nantong University, Department of Oncology, Medical School of Nantong University, Nantong, Jiangsu, China
| | - PingPing Sun
- Clinical and Translational Research Center & Institute of Oncology, Affiliated Hospital of Nantong University, Department of Oncology, Medical School of Nantong University, Nantong, Jiangsu, China
| | - Xiaojing Zhang
- Clinical and Translational Research Center & Institute of Oncology, Affiliated Hospital of Nantong University, Department of Oncology, Medical School of Nantong University, Nantong, Jiangsu, China
| | - Lei Yang
- Clinical and Translational Research Center & Institute of Oncology, Affiliated Hospital of Nantong University, Department of Oncology, Medical School of Nantong University, Nantong, Jiangsu, China
| | - Han Wu
- Department of General Surgery, Medical School of Nantong University, & Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
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