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.

Cholesterol is an essential component of the cell membrane which plays a critical role in the survival of immune and tumor cells. Reprogramming of cholesterol metabolism in both tumor cells and immune cells can impact tumor progression and anti-tumor immune responses. Strategies aimed at modulating cholesterol metabolism have been demonstrated to be effective in hindering tumor growth and boosting anti-tumor immune functions. This review provides a thorough analysis of intracellular cholesterol homeostasis regulation in cells, focusing on key genes and signaling pathways. It particularly emphasizes the regulatory mechanisms and importance of the cholesterol presence state (esterified/free), levels of cholesterol, and its metabolites in immune and tumor cells. Additionally, the review thoroughly explores how cholesterol metabolism and sources (endogenous/exogenous) in the tumor microenvironment (TME) contribute to the interplay among tumor cells, immune suppressor cells, and immune effector cells, promoting cancer progression and immune evasion. It also delves into current insights on the influence of cholesterol metabolites and related drugs in regulating tumor development or immunotherapy. Finally, it presents an overview of recent advancements in clinical and preclinical trials investigating the efficacy of targeted cholesterol metabolism treatments and combination therapies in cancer management, while proposing potential future research directions in tumor immunity. This review is poised to offer fresh perspectives and avenues for examining the potential of cancer immunotherapy centered on cholesterol metabolism regulation.

KIFC2 plays an important role in prostate cancer progression and chemotherapy resistance, but the mechanism of its involvement in other malignancies remains unclear. Therefore, this study aimed to analyze and validate the mechanism of effect of KIFC2 in multiple tumors. Bioinformatic analysis was performed in conjunction with multiple databases (The Cancer Genome Atlas, Genotype-Tissue Expression Project, Human Protein Atlas, etc.) to fully explore the potential role of KIFC2 within individual tumors and to analyze the correlation with major research components such as prognosis, mutations, and the tumor microenvironment. The expression of KIFC2 demonstrates a significant correlation with the prognosis, clinical phenotype, tumor mutational burden, microsatellite instability, and tumor microenvironment across various malignancies and is associated with the modulation of diverse functional and signaling pathways. The differences in the expression of KIFC2 in the bladder cancer tissues (14 pairs) were statistically significant. The pan-cancer analysis in this study revealed the multifunctionality of KIFC2 in a variety of tumors, indicating a possible prognostic predictor and potential therapeutic target for tumors.

N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor.

The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations.

This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.

Cholesterol is a crucial structural component of cell membranes, playing a vital role in maintaining membrane fluidity and stability. Cholesterol metabolism involves four interconnected processes: de novo synthesis, uptake, efflux, and esterification. Disruptions in any of these pathways can lead to imbalances in cholesterol homeostasis, which are significantly associated with cancer progression. In recent years, traditional Chinese medicine (TCM) has emerged as a comprehensive therapeutic approach with multi-target and multi-pathway effects, demonstrating significant potential in regulating cholesterol metabolism. Research has shown that certain components of TCM can modulate enzymes, transport proteins, and signaling pathways involved in cholesterol metabolism, effectively interfering with survival and migration of cancer. These mechanisms highlight the unique advantages of TCM in inhibiting tumor progression. In this review we systematically describe the execution and regulation of the four key cholesterol metabolism processes, highlights the roles of critical proteins involved, and provides a comprehensive overview of natural products from TCM that modulate cholesterol metabolism. This review provides valuable insights for the development of novel drugs and cancer therapeutic strategies targeting cholesterol metabolism.

Nutrient metabolisms are vitally interrelated to cancer progression and immunotherapy. However, the mechanisms by which nutrient metabolisms interact to remodel immune surveillance within the tumor microenvironment remain largely unexplored. Here it is demonstrated that methionine restriction inhibits the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol homeostasis and a potential target for cancer immunotherapy, in colorectal cancer (CRC) but not in the liver. Mechanistically, methionine is catabolized to S-adenosylmethionine (SAM), promoting mRNA transcription of PCSK9 through increased DNA methyltransferase 1 (DNMT1)-mediated DNA methylation and suppression of sirtuin 6 (SIRT6) expression. Furthermore, both PCSK9 inhibition and dietary methionine restriction (DMR) potentiate PD-1 blockade therapy and foster the infiltration of CD8+ T cells in Colon 26 tumor-bearing mice-a proficient mismatch repair (pMMR)/microsatellite stable (MSS) CRC model that exhibits limited response to anti-PD-1 therapy. Moreover, combining 5-fluorouracil (5-FU) chemotherapy with PCSK9 inhibition and PD-1 blockade further augments therapeutic efficacy for MSS CRC. The findings establish a mechanistic link between amino acid metabolism and cholesterol metabolism within the tumor microenvironment where tumor cells sense methionine to regulate PCSK9 expression, highlighting promising combination therapeutic strategies that may greatly benefit MSS CRC patients.

Abnormal metabolism is a characteristic of malignant tumors. Numerous factors play roles in the regulation of tumor metabolism. As epigenetic regulators, enhancers, especially the super-enhancers (SEs), serve as platforms for transcription factors that regulate the expression of metabolism-related enzymes or transporters at the gene level. In this study, we review the effects of enhancer/ SE-driven genes on tumor metabolism and immunity. Enhancers/SEs play regulatory roles in glucose metabolism (glycolysis, gluconeogenesis, tricarboxylic acid (TCA) cycle, pyruvate, and pentose phosphate pathway, lipid metabolism (cholesterol, fatty acid, phosphatide, and sphingolipid), and amino acid metabolism (glutamine, tryptophan, arginine, and cystine). By regulating tumor metabolism, enhancers and SEs can reprogram tumor microenvironment, especially the status of various immune cells. Therefore, interfering enhancers/SEs that regulate the tumor metabolism is likely to enhance the effectiveness of immunotherapy.

Immunotherapy has revolutionized cancer treatment, yet its efficacy is frequently compromised by metabolic mechanisms that drive resistance. Understanding how tumor metabolism shapes the immune microenvironment is essential for developing effective therapeutic strategies. This review examines key metabolic pathways influencing immunotherapy resistance, including glucose, lipid, and amino acid metabolism. We discuss their impact on immune cell function and tumor progression, highlighting emerging therapeutic strategies to counteract these effects. Tumor cells undergo metabolic reprogramming to sustain proliferation, altering the availability of essential nutrients and generating toxic byproducts that impair cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell activity. The accumulation of lactate, deregulated lipid metabolism, and amino acid depletion contribute to an immunosuppressive tumor microenvironment (TME). Targeting metabolic pathways, such as inhibiting glycolysis, modulating lipid metabolism, and restoring amino acid balance, has shown promise in enhancing immunotherapy response. Addressing metabolic barriers is crucial to overcoming immunotherapy resistance. Integrating metabolic-targeted therapies with immune checkpoint inhibitors may improve clinical outcomes. Future research should focus on personalized strategies to optimize metabolic interventions and enhance antitumor immunity.

Oxysterol binding protein-related protein 10 (OSBPL10) is a crucial sterol transporter that plays a significant role in regulating metabolic homeostasis. Previous studies have indicated that OSBPL10 promotes the development of several tumors. However, an integrative bioinformatics and immune infiltration analysis of OSBPL10 across various cancers has yet to be conducted. In this study, we comprehensively analyzed the expression patterns, prognostic value, genetic variations, protein modifications, immune infiltration characteristics, and biological functions of OSBPL10 in 33 human cancers using bioinformatics methods and publicly available databases, including TCGA, GEPIA2, GTEx, UCSC, UALCAN, HPA and TISCH2.0. The function of OSBPL10 and its associated mechanisms were confirmed in the pancreatic cancer cell lines Panc-1 and Mia PaCa-2. Our results revealed that OSBPL10 mRNA expression was significantly upregulated in 12 types of tumor tissues and downregulated in 3 cancers, which was notably associated with poor prognosis, pathological stage, and subtype in 10 tumors. Additionally, the level of promoter methylation exhibited a significant negative correlation with OSBPL10 mRNA expression. OSBPL10 expression was found to be dramatically associated with the levels of chemokines, chemokine receptors, immune checkpoints, and immune cell infiltration across various tumors by activating cancer pathways related to the extracellular matrix (ECM) and TSC/mTOR while downregulating tumor cell stemness. Furthermore, elevated OSBPL10 expression was negatively correlated with most drug sensitivities. In vitro experiments showed that OSBPL10 promoted the proliferation and migration of pancreatic cancer cells through the VEGF/AKT signaling pathway. In conclusion, our pan-cancer analysis suggests that OSBPL10 may serve as a critical biomarker for improving prognosis through OSBPL10-targeted therapies, immunotherapies, and chemotherapeutic combinations in cancer patients.

Previous studies have investigated the role of metabolic factors in risk of hematological malignancies with contradicting findings. Existing studies are generally limited by potential concern of reverse causality and confounding by inflammation. Therefore, we aimed to investigate the associations of glucose, lipid, and apolipoprotein biomarkers with the risk of hematological malignancy. We performed a study of over 560,000 individuals of the Swedish AMORIS cohort, with measurements of biomarkers for carbohydrate, lipid, and apolipoprotein metabolism during 1985-1996 and follow-up until 2020. We conducted a prospective cohort study and used Cox models to investigate the association of nine different metabolic biomarkers (glucose, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL-C/HDL-C, triglyceride (TG), apolipoprotein B (ApoB), apolipoprotein A-I (ApoA I), and ApoB/ApoA-I) with risk of hematological malignancy, after excluding the first five years of follow-up and adjustment for inflammatory biomarkers. We observed a decreased risk of hematological malignancy associated with one SD increase of TC (HR 0.93; 95% CI 0.91-0.96), LDL-C (HR 0.94; 95% CI 0.91-0.97), HDL-C (HR 0.92; 95% CI 0.86-0.99), and ApoA-I (HR 0.96; 95% CI 0.93-0.996). Our study highlights a decreased risk of hematological malignancy associated with a higher level of TC, LDL-C, HDL-C, and ApoA-I.

Cancer continues to pose remarkable medical challenges worldwide. While current cancer therapies can lead to initial clinical improvement, they are often followed by recurrence, metastasis, and drug resistance, underscoring the urgent need for innovative treatment strategies. Atorvastatin calcium (AC), a widely used lipid-lowering and anti-inflammation drug in the clinic, has shown antitumor potential. To further improve the antitumor efficacy, we developed self-assembled AC and polydopamine (PDA) nanoparticles whose surface was coated with macrophage membranes (CM) as a biomimetic drug delivery system [AC@PDA@CM (APM)]. APM showed high drug-loading capacity, excellent stability, excellent bioavailability, and tumor-targeting ability, ultimately achieving photothermal synergistic cancer immunotherapy. Our findings indicate that APM efficiently delivers AC to tumor sites while leveraging photothermal therapy (PTT) to enhance local tumor ablation and antitumor immune effect. Notably, APM mitigates tumor immunosuppression triggered by PTT through AC, suppressing the COX-2/PGE2 pathway and immune evasion signal CD47. Furthermore, APM notably reduced nonspecific distribution and side effects, which is conducive to ensuring the safety level of medication. This integrated approach boosts therapeutic efficacy and highlights the potential of APM as a multifunctional agent for cancer therapy, paving the way for future clinical applications.

Aldosterone-producing adenomas (APA), a major endocrine tumor and leading subtype of primary aldosteronism, cause secondary hypertension with high cardiometabolic risks. Despite potentially producing multiple steroid hormones, detailed cellular mechanisms in APA remain insufficiently studied. Our multiomics analysis focusing on APA with KCNJ5 mutations, which represent the most common genetic form, revealed marked cellular heterogeneity. Tumor cell reprogramming initiated from stress-responsive cells to aldosterone-producing or cortisol-producing cells, with the latter progressing to proliferative stromal-like cells. These cell subtypes showed spatial segregation, and APA exhibited genomic intratumor heterogeneity. Among the nonparenchymal cells, lipid-associated macrophages, which were abundant in APA, might promote the progression of cortisol-producing and stromal-like cells, suggesting their role in the tumor microenvironment. Intratumor cortisol synthesis was correlated with increased blood cortisol levels, which were associated with the development of vertebral fractures, a hallmark of osteoporosis. This study unveils the complex cellular ecosystem with clinical relevance in APA with KCNJ5 mutations, providing insights into tumor biology that could inform future clinical approaches.

Dysregulated lipid metabolism is linked to tumor progression. In this study, we identified Niemann-Pick C1-like 1 (NPC1L1) as a downstream effector of PKM2. In breast cancer cells, PKM2 knockout (KO) enhanced NPC1L1 expression while downregulating peroxisome proliferator-activated receptor α (PPARα) signaling pathway. PPARα and nuclear factor-E2 p45-related factor 1/2(Nrf1/2) are transcription factors regulating NPC1L1. In vitro PKM2 KO enhanced recruitment of Nrf1/2 to the NPC1L1 promoter region. Fenofibrate, a PPARα activator, promoted NPC1L1 expression; ezetimibe, an NPC1L1 inhibitor and effective Nrf2 activator, also elevated NPC1L1 expression. Combined administration of fenofibrate and ezetimibe significantly induced cytoplasmic vacuolation, and cell apoptosis. Mechanistically, this combined administration activated inositol required enzyme 1α(IRE1α) and produced the spliced form of X-box binding protein (XBP1s), which in turn enhanced lysine demethylase 6B (KDM6B) transcription. XBP1s interacts with KDM6B to activate genes involved in the unfolded protein response by demethylating di- and tri-methylated lysine 27 of histone H3 (H3K27), consequently increasing H3K27 acetylation levels in breast cancer cell lines. Fenofibrate and ezetimibe synergistically inhibited tumor growth in vivo. Our findings reveal that dual targeting of PPARα and NPC1L1 may represent a novel therapeutic regimen for breast cancer therapy.

Chemotherapy is widely used clinically, however, its efficacy is often compromised by the development of drug resistance, which arises from prolonged administration of drugs or other stimuli. One of the driven causes of drug resistance in tumors or bacterial infections is metabolic reprogramming, which alters mitochondrial metabolism, disrupts metabolic pathways and causes ion imbalance. Bioactive peptide materials, due to their biocompatibility, diverse bioactivities, customizable sequences, and ease of modification, have shown promise in overcoming drug resistance. This review provides an in-depth analysis of metabolic reprogramming and associated microenvironmental changes that contribute to drug resistance in common tumors and bacterial infections, suggesting potential therapeutic targets. Additionally, we explore peptide-based materials for regulating metabolism and their potential synergic effect with other therapies, highlighting the mechanisms by which these peptides reverse drug resistance. Finally, we discuss future perspectives and the clinical challenges in peptide-based treatments, aiming to offer insights for overcoming drug-resistant diseases.

Disulfiram/Cu(DSF/Cu) has a known pharmacokinetic and safety profile, exerting a strong antitumor effect. Oral tyrosine kinase inhibitors including lenvatinib are approved as first-line therapy for treating advanced unresectable hepatocellular carcinoma (HCC). These patients still have limited survival due to drug resistance. Disulfiram/Cu and lenvatinib are the promising antitumor treatments. In this study, we studied whether Disulfiram/Cu increased lenvatinib sensitivity in HCC cells. Moreover, the potential drug targets of Disulfiram/Cu and associated mechanisms were explored. We mainly investigated Autophagic flux was determined via immunofluorescence analysis and confocal microscopy. p-PI3K, p-AKT, p62, LC3B, FOXO6, and CHKA proteins associated with autophagy were detected by immunoblotting. In addition, antitumour activity of Disulfiram/Cu in combination with lenvatinib was examined in vivo through construction of the nude mouse transplant tumor model. Furthermore, our results show disulfiram/Cu combined with lenvatinib exerted the synergistic impact on treating HCC in vitro. Mechanistically, transcriptome combined with metabolome reveals Disulfiram/Cu targeting FOXO6 induction of autophagy mediated inhibits cell growth in hepatocellular carcinoma by downregulating CHKα for inhibiting AKT pathway activation while blocking choline metabolic reprogramming in HCC. These effects mostly explain the tumor-promoting effect of FOXO6 on HCC. In general, the results illustrate the mechanistic associations between metabolites and tumor cell malignant phenotype, contributing to developing new anti-HCC pharmacological treatments by Inhibiting FOXO6 for disrupting choline metabolic pathway.

Lipid accumulation is a frequently observed characteristic of cancer. Lipid accumulation is closely related to tumor progression, metastasis, and drug resistance; however, the mechanism underlying lipid metabolic reprogramming in tumor cells is not fully understood. Yin yang 2 (YY2) is a C2H2‑zinc finger transcription factor that exerts tumor-suppressive effects. However, its involvement in tumor cell lipid metabolic reprogramming remains unclear. In the present study, we identified YY2 as a novel regulator of cholesterol metabolism. We showed that YY2 suppressed cholesterol accumulation in hepatocellular carcinoma (HCC) cells by downregulating the transcriptional activity of cytochrome P450 family 51 subfamily A member 1 (CYP51A1), a key enzyme in de novo cholesterol biosynthesis. Subsequently, through in vitro and in vivo experiments, we demonstrated that this downregulation is crucial for the YY2 tumor suppressive effect. Together, our findings unraveled a previously unprecedented regulation of HCC cells cholesterol metabolism, and eventually, their tumorigenic potential, through YY2 negative regulation on CYP51A1 expression. This study revealed a novel regulatory mechanism of lipid metabolic reprogramming in tumor cells and provided insights into the molecular mechanism underlying the YY2 the suppressive effect. Furthermore, our findings suggest a potential antitumor therapeutic strategy targeting cholesterol metabolic reprogramming using YY2.

Over the past few decades, immunotherapy has emerged as a powerful strategy to overcome the limitations of conventional cancer treatments. The use of extracellular vesicles, particularly exosomes, which carry cargoes capable of modulating the immune response, has been extensively explored as a potential therapeutic approach in cancer immunotherapy. Exosomes can deliver their cargo to target cells, thereby influencing their phenotype and immunomodulatory functions. They exhibit either immunosuppressive or immune-activating characteristics, depending on their internal contents. These exosomes originate from diverse cell sources, and their internal contents can vary, suggesting that there may be a delicate balance between immune suppression and stimulation when utilizing them for immunotherapy. Therefore, a thorough understanding of the molecular mechanisms underlying the role of exosomes in cancer progression is essential. This review focuses on the molecular mechanisms driving exosome function and their impact on the tumor microenvironment (TME), highlighting the intricate balance between immune suppression and activation that must be navigated in exosome-based therapies. Additionally, it underscores the challenges and ongoing efforts to optimize exosome-based immunotherapies, thereby making a significant contribution to the advancement of cancer immunotherapy research.

B cells have crucial roles in the initiation and progression of many pathological conditions, and several therapeutic strategies have targeted the function of these cells. The advent of immunometabolism has provided compelling evidence that the metabolic reprogramming of immune cells can dramatically alter physiopathological immune activities. A better knowledge of the metabolic profiles of B cells can provide valuable means for developing therapies tuning defined cell pathways. Here we review the cellular and molecular mechanisms by which immunometabolism controls the physiology and pathophysiology of B cells and discuss the experimental evidence linking B cell metabolism to health, autoimmunity, and cancer. Considering that several metabolic pathways in B cells are involved differently, or even in opposite ways, in health and disease, we discuss how targeted modulation of B cell immunometabolism could be exploited mechanistically to rebalance abnormal B cell functions that have become altered in disease states.

Nanozymes, nanomaterials with intrinsic enzyme activity, have garnered significant attention in recent years due to their catalytic abilities comparable to natural enzymes, cost-effectiveness, high catalytic activities, and stability against environmental fluctuations. As functional analogs of natural enzymes, nanozymes participate in various critical metabolic processes, including glucose metabolism, lactate metabolism, and the maintenance of redox homeostasis, all of which are essential for normal cellular functions. However, disruptions in these metabolic pathways frequently promote tumorigenesis and progression, making them potential therapeutic targets. While several therapies targeting tumor metabolism are currently in clinical or preclinical stages, their efficacy requires further enhancement. Consequently, nanozymes that target tumor metabolism are regarded as a promising therapeutic strategy. Despite extensive studies investigating the application of nanozymes in tumor metabolism, relevant reviews are relatively scarce. This article first introduces the physicochemical properties and biological behaviors of nanozymes. Subsequently, we analyze the role of nanozymes in tumor metabolism and explore their potential applications in tumor therapy. In conclusion, this review aims to foster innovative research in related fields and advance the development of nanozyme-based strategies for cancer diagnostics and therapeutics.

The prognostic role of preoperative inflammation-nutrition-related markers in locally advanced lip squamous cell carcinoma (LSCC) remains underexplored. This study aimed to assess the impact of various preoperative inflammation-nutrition-related markers on the prognosis of patients with locally advanced LSCC undergoing surgical treatment and to establish a corresponding predictive model.

A retrospective analysis was performed on the clinical data of 169 patients with locally advanced LSCC who underwent surgical treatment. A total of 27 clinicopathological variables, including inflammation-nutrition-related markers, were collected. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors for disease-free survival (DFS) and overall survival (OS). The nomogram models were validated using receiver operating characteristic (ROC) curve analysis, calibration plots, and decision curve analysis (DCA). Risk stratification was performed based on the nomogram scores, and differences between risk subgroups were explored.

The extranodal extension (ENE), surgical safety margin, Glasgow prognostic score (GPS), Geriatric Nutritional Risk Index (GNRI), Controlling Nutrition score (CONUT), American Joint Committee on Cancer (AJCC) stage, and adjuvant radiotherapy were independent prognostic factors for DFS. In contrast, ENE, surgical safety margin, GNRI, CONUT, AJCC stage, and adjuvant radiotherapy were also independent prognostic factors for OS. The nomograms demonstrated better predictive performance than the AJCC staging system. Based on the nomogram model, patients were stratified into low-, medium-, and high-risk subgroups, which exhibited significant differences in survival outcomes.

GPS, GNRI, and CONUT are independent factors affecting the prognosis of patients with locally advanced LSCC undergoing radical surgery. By combining GPS, GNRI, and COUNT with other independent clinicopathological prognostic factors, a reliable nomogram model can be established to accurately predict patients' DFS and OS. This provides a powerful tool for individualized prognostic assessment, optimized risk stratification, and treatment decision-making.

The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK family SNF1-like kinase 1 (NUAK1) is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by spliced form of X-box binding protein 1 (XBP1s) downstream of ICD-induced endoplasmic reticulum (ER) stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampens ROS and ICD, and therefore also dampens tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.

Oxidative stress is a common event involved in cancer pathophysiology, frequently accompanied by unique lipid metabolic reprogramming phenomena. Oxidative stress is caused mainly by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant system in cancer cells. Emerging evidence has reported that oxidative stress regulates the expression and activity of lipid metabolism-related enzymes, leading to the alteration of cellular lipid metabolism; this involves a significant increase in fatty acid synthesis and a shift in the way in which lipids are taken up and utilized. The dysregulation of lipid metabolism provides abundant intermediates to synthesize biological macromolecules for the rapid proliferation of cancer cells; moreover, it contributes to the maintenance of intracellular redox homeostasis by producing a variety of reducing agents. Moreover, lipid derivatives and metabolites play critical roles in signal transduction within cancer cells and in the tumor microenvironment that evades immune destruction and facilitates tumor invasion and metastasis. These findings suggest a close relationship between oxidative stress and lipid metabolism during the malignant progression of cancers. This review focuses on the crosstalk between the redox system and lipid metabolic reprogramming, which provides an in-depth insight into the modulation of ROS on lipid metabolic reprogramming in cancers and discusses potential strategies for targeting lipid metabolism for cancer therapy.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide, characterized by a dismal prognosis and elusive therapeutic targets. Dysregulated cholesterol metabolism is a critical hallmark of cancer cells, facilitating tumor progression. Here, using whole genome sequencing data from several ESCC cohorts, we identified the important role of squalene epoxidase (SQLE) in promoting ESCC tumorigenesis and metastasis. Specifically, our findings highlight the significance of 2,3-oxidosqualene, an intermediate metabolite of cholesterol biosynthesis, synthesized by SQLE and metabolized by lanosterol synthase (LSS), as a key regulator of ESCC progression. Mechanistically, the interaction between 2,3-oxidosqualene and vinculin enhances the nuclear accumulation of Yes-associated protein 1 (YAP), thereby increasing YAP/TEAD-dependent gene expression, and accelerating both tumor growth and metastasis. In a 4-nitroquinoline 1-oxide (4-NQO)-induced ESCC mouse model, overexpression of Sqle resulted in accelerated tumorigenesis compared to wild-type controls, highlighting the pivotal role of SQLE in vivo. Furthermore, elevated SQLE expression in ESCC patients correlates with poorer prognoses, suggesting potential therapeutic avenues for ESCC treatment. In conclusion, our study elucidates the oncogenic function of 2,3-oxidosqualene as a naturally occurring metabolite and proposes modulation of its levels as a promising therapeutic strategy for ESCC.

The Hippo pathway in the tumorigenesis and progression of PDAC, with lysophosphatidic acid (LPA) regulating the Hippo pathway to facilitate cancer progression. However, the impact of the Hippo signaling pathway on tumor repopulation in PDAC remains unreported.

Direct and indirect co-culture models to investigate gemcitabine-induced apoptotic cells can facilitate the repopulation of residual tumor cells. Mass spectrometry analysis was conducted to assess the impact of gemcitabine treatment on the lipid metabolism of pancreatic cancer cells. ELISA assays confirmed gemcitabine promotes the release of LPA from apoptotic pancreatic cancer cells. The expression of Yes-associated protein 1 (YAP1) elucidated the underlying mechanism by which dying cells induce tumor repopulation using qRT-PCR and Western blot. We studied the biological function of pancreatic cancer cells using CCK-8, colony formation, and transwell invasion assays in vitro. Co-culture models were used to validate the impact of Hippo pathway on tumor repopulation, while flow cytometry was employed to assess the sensitivity of pancreatic cancer cells to gemcitabine in the context of Hippo pathway.

Gemcitabine-induced dying cells released LPA in a dose-dependent manner, which promoted the proliferation, clonal formation, and invasion of pancreatic cancer cells. Mechanistic studies showed that gemcitabine and LPA facilitated the translocation of YAP1 and induced the inactivation of the Hippo pathway. YAP1 overexpression significantly enhanced the activity of autotaxin, leading to stimulated pancreatic cancer cells to secrete LPA. This mechanism orchestrated a self-sustaining LPA-Hippo feedback loop, which drove the repopulation of residual tumor cells. Simultaneously, it was observed that suppressing LPA and YAP1 expression enhanced the sensitivity of pancreatic cancer cells to gemcitabine.

Our investigation indicated that targeting the LPA-YAP1 signaling pathway could serve as a promising strategy to augment the overall therapeutic efficacy against PDAC.

Recent studies have demonstrated that chronic stress can enhance the development of multiple human diseases, including cancer. However, the role of chronic stress in esophageal carcinogenesis and its underlying molecular mechanisms remain unclear. This study uncovered that dysregulated cholesterol metabolism significantly promotes esophageal carcinogenesis under chronic stress conditions. Our findings indicate that the persistent elevation of glucocorticoids induced by chronic stress stimulates cholesterol uptake, contributing to esophageal carcinogenesis. The activated glucocorticoid receptor (GCR) enrichment at the promoter region of High Mobility Group Box 2 (HMGB2) facilitates its transcription. As a transcription coactivator, HMGB2 enhances Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1) transcription and regulates cholesterol metabolism through LDL particle uptake into cells via Low Density Lipoprotein Receptor (LDLR). These results emphasize the significant impact of chronic stress on esophageal carcinogenesis and establish cholesterol metabolism disorder as a crucial link between chronic stress and the development of ESCC. The implications suggest that effectively managing chronic stress may serve as a viable strategy for preventing and treating ESCC.

The immunosuppressive residual tumor microenvironment (IRTM) is a key factor in the high recurrence and metastasis rates of hepatocellular carcinoma (HCC) after microwave ablation (MWA). Cholesterol-rich tumor fragments significantly contribute to IRTM deterioration. This study developed a cholesterol-targeted catalytic hydrogel, DA-COD-OD-HCS, to enhance the synergy between MWA and immune checkpoint inhibitors (ICIs) for HCC treatment. Cholesterol oxidase (COD), modified with dimethyl maleic anhydride (DA) for release in acidic IRTM, is used to degrade cholesterol. Oxydextran (OD) and hemin-chitosan (HCS) formed a dual network gel, ensuring long-term fixation of COD and hemin in the IRTM post-MWA. In both in vitro and in vivo HCC models, DA-COD-OD-HCS effectively released COD, degraded cholesterol, and induced tumor cell ferroptosis, enhancing the antitumor immune response. Combined with anti-PD-L1 immunotherapy, this strategy inhibited primary tumor growth and distant metastases, without side effects on adjacent tissues. This work highlights that cholesterol-targeting catalytic hydrogels fueled by tumor debris can significantly improve the efficacy of MWA and ICIs, offering a novel therapeutic approach for HCC.

Triple-negative breast cancer (TNBC) is known for frequent copy number alterations (CNAs) and metabolic reprogramming. However, the mechanism by which CNAs of metabolic genes drive distinct metabolic reprogramming and affect disease progression remains unclear. Through an integrated analysis of our TNBC multiomic dataset (n = 465) and subsequent experimental validation, we identify copy number amplification of the metabolic gene flavin-adenine dinucleotide synthetase 1 (FLAD1) as a crucial genetic event that drives TNBC progression. Mechanistically, FLAD1, but not its enzymatically inactive mutant, upregulates the enzymatic activity of FAD-dependent lysine-specific demethylase 1 (LSD1). LSD1 subsequently promotes the expression of sterol regulatory element-binding protein 1 (SREBP1) by demethylating dimethyl histone H3 lysine 9 (H3K9me2). The upregulation of SREBP1 enhances the expression of lipid biosynthesis genes, ultimately facilitating the progression of TNBC. Clinically, pharmacological inhibition of the FLAD1/LSD1/SREBP1 axis effectively suppresses FLAD1-induced tumor progression. Moreover, LSD1 inhibitor enhances the therapeutic effect of doxorubicin and sacituzumab govitecan (SG). In conclusion, our findings reveal the CNA-derived oncogenic signalling axis of FLAD1/LSD1/SREBP1 and present a promising treatment strategy for TNBC.

Anti-programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) immunotherapy has shown promising results in cancer treatment, improving clinical outcomes and prolonging patient survival. However, most patients exhibit low response rates to PD-1/PD-L1 blockade, highlighting the urgent need for new enhancers. Increasing data now demonstrate that inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine proteinase, can enhance the antitumor efficacy of anti-PD-1/PD-L1 immunotherapy.

The aim of the present study was to investigate the effects of targeting the mevalonate pathway (MVP) in rhabdomyosarcoma (RMS), a soft tissue tumor with a prevalence in young people.

In silico analyses of RNA datasets were performed to correlate MVP with RMS patient survival. The sensitivity of RMS cell lines to MVP inhibitors was assessed in vitro by analysis of cell growth (crystal violet and clonogenic assays), cell migration (wound healing assay), cell survival (neutral red assay), and oxidative stress (ROS assay). The effects of MVP inhibitors were tested in vivo by analyzing RMS xenografts grown in NOD/SCID mice. Quantification of protein targets was performed using immunoblotting or immunohistochemistry analyses.

In silico analysis showed upregulation of sterol regulatory element-binding protein 2 (SREBP2) and MVP genes, including 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), farnesyl-diphosphate synthase (FDPS), squalene epoxidase (SQLE), which correlated with worse overall patient survival. Targeting of MVP in human RD and RH30 lines by inhibitors of SREBP2 (fatostatin), HMGCR (lovastatin and simvastatin), and FDPS (zoledronic acid) resulted in impaired cell growth, migration, and viability, and increased oxidative cell death in combination with actinomycin D. Conversely, cholesterol (CHO) supplementation enhanced cell growth and migration. Fatostatin and lovastatin produced rapid attenuation of Erk1/2 and Akt1 signaling in RMS lines, and oral administration of lovastatin reduced tumor mass growth of xenografted RD cells in NOD/SCID mice. Finally, we found that forced Akt1 activation in RD cells was sufficient to drive SREBP2, HMGCR and SQLE protein expression, promoting increased susceptibility to MVP inhibitors.

These data suggest that the Akt1, SREBP2 and MVP axis is critical for RMS tumor growth, migration, and oxidative stress protection primarily through maintaining adequate CHO levels that enable proper intracellular signaling. Therefore, stimulating CHO depletion via SREBP2 and MVP inhibition may represent a viable option to improve the combination therapy protocol, especially in pAkt1-positive RMS.

Some cancers have been found to require abundant supplies of lipids for their development. One example is prostate cancer (PCa). To date, lipid-modifying factors, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like 3 protein (ANGPTL3), and lipoprotein(a) or Lp(a), have not been reported in men with PCa. The present study aimed to verify whether plasma levels of these lipid-related proteins vary in men with PCa compared to at-risk but cancer-free men.

Plasma samples from 35 men with locally advanced PCa Gleason 8 and 9 versus 35 men at risk of PCa were selected as cases and controls. Blood samples were paired according to age and BMI. Apolipoprotein B100 (Apo B), Lp(a), and lipid profiles were measured on an analytical platform (Roche Cobas). PCSK9 and ANGPTL3 levels were determined by ELISA.

No significant change in lipids and related factors levels was observed between men with localized PCa Gleason 8 or 9 and matched controls. A correlation between ANGPTL3 and HDL levels was only confirmed in controls (ρ = 0.54, p = 0.0009). PCSK9 was inversely associated with PSA levels in the entire cohort (ρ = -0.31, p < 0.01), suggesting that factors influencing PCSK9 could also influence PSA levels. In controls only, PSA levels were correlated with LDL, Apo B, non-HDL, total cholesterol, and triglycerides (all ρ coefficients ≥ 0.35, all p-values < 0.05). PCSK9 was correlated to LDL in PCa men, but the relationship was unexpectedly found to be inverse.

In this observational study, lipid profiles, PCSK9, ANGPTL3, and Lp(a) levels did not change in men diagnosed with locally advanced Gleason 8 or 9 PCa compared to at-risk but cancer-free men. The present data suggest a complex interplay between PCSK9, PSA, and the lipid profile in localized PCa.

Tumor progression is associated with tumor-cell softening. Improving the stiffness of the tumor cells can make them more vulnerable to lymphocyte-mediated attack. Tumor cell membranes typically exhibit higher cholesterol levels than normal cells, making tumor cells soft. Herein, we demonstrate a mechanical immune checkpoint inhibitor (MICI) formulated by cyclodextrin (CD) lipids and fusogenic lipids. Through fusing CD lipids into the tumor cell membrane using a fusogenic liposome formulation, the cholesterol in the plasma membrane is reduced due to the specific host-guest interactions between CD lipid and cholesterol. As a result, tumor cells are stiffened, and the activation of lymphocytes (including NK and cytotoxic effector T cells) is improved when contacting the stiffened tumor cells, characterized by robust degranulation and effector cytokine production. Notably, this treatment has negligible influence on the infiltration and proliferation of lymphocytes in tumor tissues, confirming that the enhanced antitumor efficacy should result from activating a specific number of lymphocytes caused by direct regulation of the tumor cell stiffness. The combination of MICIs and clinical immunotherapies enhances the lymphocyte-mediated antitumor effects in two tumor mouse models, including breast cancer and melanoma. Our research also reveals an unappreciated mechanical dimension to lymphocyte activation.

Recently, there has been burgeoning interest in the involvement of cholesterol metabolism in cancer. Squalene epoxidase (SQLE), as a critical rate-limiting enzyme in the cholesterol synthesis pathway, has garnered attention due to its overexpression in various cancer types, thereby significantly impacting tumor prognosis and resistance mechanisms. Firstly, SQLE contributes to unfavorable prognosis through diverse mechanisms, encompassing modulation of the PI3K/AKT signaling pathway, manipulation of the cancer microenvironment, and participation in ferroptosis. Secondly, directing efforts towards targeting SQLE, via mechanisms such as the PI3K/AKT pathway, presents promising avenues for overcoming resistance to conventional therapies such as endocrine cancer therapy, chemotherapy, immunotherapy, or radiotherapy. Moreover, the effectiveness of SQLE protein inhibitors in impeding cancer progression may either depend directly on SQLE inhibition or function through alternative pathways separate from SQLE. This mini-review offers insights into the intricate mechanisms through which SQLE affects the prognosis and resistance profiles across diverse cancer types, while succinctly elucidating the mechanisms underpinning the anticancer effects of SQLE protein inhibitors. Furthermore, this mini-review underscores the necessity for further investigations into the interplay between SQLE and cancer, proposing potential avenues for future research, with the aim of serving as a reference for exploring the mechanisms governing the role of SQLE in cancer regulation.

Gut microbiota plays a pivotal role in various health challenges, particularly in mitigating diabetes-induced renal damage. Numerous studies have highlighted that modifying gut microbiota is a promising therapeutic strategy for preserving kidney function and mitigating diabetes-related complications. This study aimed to evaluate the protective effects of Lactobacillus acidophilus ATCC 4356 supplementations on kidney health in a rat model of diabetes-induced renal damage. Four groups were studied: control, probiotic supplementation, diabetic, and diabetic with probiotic supplementation. Diabetes was induced using a single streptozotocin (STZ) injection after a 12 h fast, and probiotic supplementation (1 × 10⁹ CFU/kg daily) was administered two weeks prior to diabetes induction and continued throughout the experimental period. Weekly assessments included fasting blood glucose, insulin, glycation markers, and kidney function tests. Glucose metabolism and insulin sensitivity were analyzed through oral glucose tolerance test (OGTT) and insulin sensitivity test (IST). The microbiome was analyzed using 16S rRNA gene sequencing to evaluate changes in diversity and composition. Probiotic supplementation significantly enhanced microbial diversity and composition. Alpha diversity indices such as Shannon and Chao1 demonstrated higher values in the probiotic-treated diabetic group compared to untreated diabetic rats. The Firmicutes/Bacteroidetes ratio, a key indicator of gut health, was also restored in the probiotic-treated diabetic group. Results: Probiotic supplementation significantly improved glycemic control, reduced fasting blood glucose levels, and enhanced insulin sensitivity in diabetic rats. Antioxidant enzyme levels, depleted in untreated diabetic rats, were restored, reflecting reduced oxidative stress. Histological analysis showed better kidney structure, reduced inflammation, and decreased fibrosis. Furthermore, the Comet assay results confirmed a reduction in DNA damage in probiotic-treated diabetic rats. Conclusion: Lactobacillus acidophilus ATCC 4356 supplementation demonstrated significant protective effects against diabetes-induced renal damage by restoring gut microbiota diversity, improving glycemic control, and reducing oxidative stress. These findings highlight the potential of targeting the gut microbiota and its systemic effects on kidney health as a therapeutic approach for managing diabetes-related complications. Further research is needed to optimize probiotic treatments and assess their long-term benefits in diabetes management and kidney health.