Lipid metabolism has been increasingly recognized to play an influencing role in tumor initiation, progression, metastasis, and therapeutic drug resistance. Targeting lipid metabolic reprogramming represents a promising therapeutic strategy. Despite their structural complexity and poor targeting efficacy, lipid-metabolizing drugs, either used alone or in combination with chemotherapeutic agents, have been employed in clinical practice. The advent of nanotechnology offers new approaches to enhancing therapeutic effects, includingthe targeted delivery and integration of lipid metabolic reprogramming with chemotherapy, photodynamic therapy (PDT), and immunotherapy. The integrated nanoformulation, nanomedicine, could significantly advance the field of lipid metabolism therapy. In this review, we will briefly introduce the concept of cancer lipid metabolism reprogramming, then elaborate the latest advances in engineered nanomedicine for targeting lipid metabolism during cancer treatment, and finally provide our insights into future perspectives of nanomedicine for interference with lipid metabolism in the tumor microenvironment.

Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME), actively contributing to the formation of an immunosuppressive niche that fosters tumor progression. Consequently, there has been a growing interest in targeting TAMs as a promising avenue for cancer therapy. Recent advances in the field of immunometabolism have shed light on the influence of metabolic adaptations on macrophage physiology in the context of cancer. Here, we discuss the key metabolic pathways that shape the phenotypic diversity of macrophages. We place special emphasis on how metabolic reprogramming impacts the activation status of TAMs and their functions within the TME. Additionally, we explore alterations in TAM metabolism and their effects on phagocytosis, production of cytokines/chemokines and interaction with cytotoxic T and NK immune cells. Moreover, we examine the application of nanomedical approaches to target TAMs and assess the clinical significance of modulating the metabolism of TAMs as a strategy to develop new anti-cancer therapies. Taken together, in this comprehensive review article focusing on TAMs, we provide invaluable insights for the development of effective immunotherapeutic strategies and the enhancement of clinical outcomes for cancer patients.

Tumour-associated macrophages (TAMs) contribute to hepatocellular carcinoma (HCC) progression. However, while the pro-tumour and immunosuppressive roles of lipid-loaded macrophages are well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear.

Single-cell RNA sequencing was performed on mouse and human HCC tumour samples to elucidate the landscape of HCC TAMs. Macrophages were stimulated with various long-chain unsaturated fatty acids (UFAs) to assess immunosuppressive molecule expression in vitro. Additionally, in vivo and in vitro studies were conducted using mice with macrophage-specific deficiencies in fatty acid-binding protein 5 (FABP5) or peroxisome proliferator-activated receptor γ (PPARγ).

Single-cell RNA sequencing identified a subpopulation of FABP5+ lipid-loaded TAMs characterized by enhanced immune checkpoint blocker ligands and immunosuppressive molecules in an oncogene-mutant HCC mouse model and human HCC tumours. Mechanistically, long-chain UFAs released by tumour cells activate PPARγ via FABP5, resulting in immunosuppressive properties in TAMs. FABP5 deficiency in macrophages decreases immunosuppressive molecule expression, enhances T cell-dependent antitumour immunity, diminishes HCC growth, and improves immunotherapy efficacy.

This study demonstrates that UFAs promote tumourigenesis by enhancing the immunosuppressive tumour microenvironment via FABP5-PPARγ signalling and provides a proof-of-concept for targeting this pathway to improve the efficacy of tumour immunotherapy.

Despite the role of tumour-associated macrophages (TAMs) in promoting tumour progression being well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear. Our study reveals that FABP5-mediated unsaturated fatty acid metabolism in TAMs is crucial for modulating antitumour T-cell immunity and influencing the efficacy of immunotherapy. This finding provides novel insights into the immunomodulatory roles of FABP5+ lipid-loaded TAMs in hepatocellular carcinoma and suggests that targeting FABP5 could offer a new approach to liver cancer treatment.

Tumor-associated macrophages (TAM) have been shown to regulate colon cancer (CC) progression. However, it is not clear whether tumor-derived exosomal circular RNA (circRNA) regulates TAM to influence CC progression. The expression levels of circ_0020095, M1 macrophage markers, M2 macrophage markers, and interleukin-1 receptor-associated kinase 1 (IRAK1) were determined by qRT-PCR. Cell proliferation, migration and invasion were examined by EdU assay, wound healing assay and transwell assay. Exosomes derived from CC cells were used to treat M0 macrophages. M1 macrophage surface marker CD86 was detected by flow cytometry, and protein expression was examined by western blot. Then, the medium of exosome-treated M0 macrophages was used to culture CC cells to determine CC cell functions. RNA pull-down assay, RIP assay and dual-luciferase reporter assay were performed to validate interaction. Circ_0020095 had elevated expression in CC tissues and cells, and its knockdown repressed CC cell proliferation and metastasis. M0 macrophages could take by CC cell-derived exosomes to regulate circ_0020095 expression. Exosomal circ_0020095 restrained M1 macrophage polarization and increased M2 macrophage polarization to enhance CC cell progression. Besides, IRAK1 silencing could promote CC cell proliferation and metastasis by inhibiting M1 macrophage polarization, and its overexpression also abolished the effect of exosomal circ_0020095. Mechanistically, circ_0020095 could competitively bind to IGF2BP1 and then reduced the binding ability of IGF2BP1 and IRAK1 3'UTR. Tumor-derived exosomal circ_0020095 promoted CC cell progression via inhibiting M1 macrophage polarization through IGF2BP1/IRAK1 axis.

Macrophages are myeloid cells that receive, integrate, and respond to tumoral cues. Tumors evolve and are shaped by macrophages, with tumor-associated macrophage (TAM)-tumor sculpting capacities going beyond an increase in their cellular mass. Longitudinal and local heterogeneity of TAM states is now possible with the use of single-cell and spatial transcriptomics. However, understanding TAM biology and its fundamental functional programs is still challenging, probably because of the lack of models that fully integrate TAM complexity. Here, we aim to review TAM diversity not only at the level of single-cell phenotypes but also by integrating complex physiological signals that determine their complexity and plasticity in tumors.

While highlighting the complexity and heterogeneity of tumor immune microenvironments, the application of single-cell analyses in human cancers has identified recurrent subsets of tumor-associated macrophages (TAMs). Among these, interleukin (IL)-1β+ TAMs - cells with high levels of expression of inflammatory response and tissue repair genes, but with limited capacity to stimulate cytotoxic immunity - are emerging as key drivers of pathogenic inflammation in cancer. In this review we discuss recent literature defining the phenotypical, molecular, and functional properties of IL-1β+ TAMs, as well as their temporal dynamics and spatial organization. Elucidating the biology of these cells across tumor initiation, progression, metastasis, and therapy could inform the design and interpretation of clinical trials targeting IL-1β and/or other inflammatory factors in cancer immunotherapy.

The peritoneal cavity (PerC) constitutes a distinct anatomical compartment that harbors various subpopulations of peritoneal macrophages. However, there remains a significant gap in our understanding of the functions of these macrophage subpopulations in the context of peritoneal metastasis of colorectal cancer (PM-CRC) and their roles in the tumor progression process. This investigation seeks to analyze the characteristics of large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs), in the context of PM-CRC.

A murine model of PM-CRC was developed through the intraperitoneal administration of the MC38 colorectal cancer cell line into C57BL/6 mice. Peritoneal effusions were subsequently collected at various time points post-injection and subjected to analysis via flow cytometry, cell co-culture assays, among other techniques. Additionally, clodronate liposomes were employed to deplete peritoneal macrophages in order to investigate the impact of SPMs on tumor progression and survival in the PM-CRC mouse model.

The findings of this study demonstrated a significant increase in the number of SPMs during the progression of PM-CRC, concomitant with a decrease in the proportion of LPMs. Notably, SPMs exhibited a macrophage phenotype conducive to tumor growth. In the PM-CRC mouse model, the dynamic escalation of SPMs following lipopolysaccharide stimulation was associated with a reduced survival rate. However, the depletion of SPMs using clodronate liposomes in the later stages of the model effectively extended the survival period in cases of PM-CRC.

The findings of this study suggest that SPMs acts as a catalyst in the progression of peritoneal metastasis in colorectal cancer, thereby identifying it as a potential therapeutic target for managing this condition.

A major characteristic of ovarian cancer (OC) is its unique route of metastasis via ascites. The immune microenvironment in ascites remains understudied, leaving the mechanism of ascites-mediated abdominal metastasis obscure. Here, a single-cell transcriptomic landscape of CD45+ immune cells across multiple anatomical sites is depicted, including primary tumors, metastatic lesions, and ascites, from patients diagnosed with high-grade serous ovarian carcinoma (HGSOC). A novel subset of perilipin 2 high (PLIN2hi) macrophages are identified that are enriched in ascites and positively correlated with OC progression, hence being designated as "ascites-associated macrophages (AAMs)". AAMs are lipid-loaded with overexpression of the lipid droplet protein PLIN2. Overexpression or suppression of PLIN2 can enhance or inhibit tumor cell migration, invasion, and vascular permeability in vitro, which is also confirmed in vivo. Mechanistically, it is demonstrated that PLIN2 boosts HIF1α/SPP1 signaling in macrophages, thereby exerting pro-tumor functions. Finally, a PLIN2-targeting liposome is designed to efficiently suppress ascites production and tumor metastasis. Taken together, this work provides a comprehensive characterization of the cancer-promoting function and lipid-rich property of ascites-enriched PLIN2hi macrophages, establishes a link between lipid metabolism and hypoxia within the context of the ascites microenvironment, and elucidates the pivotal role of ascites in trans-coelomic metastasis of OC.

The potential oncogenic role of Baculoviral inhibitor of apoptosis (IAP) Repeat-Containing (BIRC) genes in prostate cancer (PCa) has yet to be fully investigated. Two genes associated with disease recurrence, BIRC5 and BIRC7, were identified through survival analysis, and prostate cancer patients were categorized into two subtypes, C1 and C2, based on these genes. We performed survival analyses to assess the relationship between subtypes and the prognosis of PCa. Single-cell dataset analysis was used to identify specific cell types with enriched expression of BIRC family genes. Our findings show that BIRC5 and BIRC7 exhibit higher expression in PCa tissues compared to non-cancerous tissues. High expression of BIRC5 and BIRC7 independently correlates with an adverse prognosis in PCa. The analysis of mechanisms reveals that the differentially expressed genes impact signaling pathways associated with cancer and immunity. BIRC5/BIRC7 correlate with several immune cells infiltrating levels including T cells and macrophages. Furthermore, our research indicates that elevated expression of BIRC5 is associated with immune infiltration in PCa. These findings highlight the potential of BIRC5/BIRC7 or C1 subtype as prognostic biomarkers, offering new insights into possible targets for the development of therapeutic biomarkers and immunotherapeutic for PCa.

Macrophages are heterogeneous cells that are the mediators of tissue homeostasis. These immune cells originated from monocytes and are classified into two basic categories, M1 and M2 macrophages. M1 macrophages exhibit anti-tumorous inflammatory reactions due to the behavior of phagocytosis. M2 macrophages or tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and have a basic role in tumor progression by interacting with other immune cells in TME. By the expression of various cytokines, chemokines, and growth factors, TAMs lead to strengthening tumor cell proliferation, angiogenesis, and suppression of the immune system which further support invasion and metastasis. This review discusses recent and updated mechanisms regarding tumor progression by M2 macrophages. Moreover, the current therapeutic approaches targeting TAMs, their advantages, and limitations are also summarized, and further treatment approaches are outlined along with an elaboration of the tumor regression role of macrophages. This comprehensive review article possibly helps to understand the mechanisms underlying the tumor progression and regression role of macrophages in a comparative way from a basic level to the advanced one.

Lipid metabolism in cancer is characterized by dysregulated lipid regulation and utilization, critical for promoting tumor growth, survival, and resistance to therapy. Pancreatic cancer (PC) is a highly aggressive malignancy of the gastrointestinal tract that has a dismal 5-year survival rate of less than 10%. Given the essential function of the pancreas in digestion, cancer progression severely disrupts its function. Standard treatments for PC such as surgical resection, chemotherapy, and radiotherapy. However, these therapies often face significant challenges, including biochemical recurrence and drug resistance.Given these limitations, new therapeutic approaches are being developed to target tumor metabolism. Dysregulation of cholesterol biosynthesis and alterations in fatty acids (FAs), such as palmitate, stearate, omega-3, and omega-6, have been observed in pancreatic cancer. These lipids serve as energy sources, signaling molecules, and essential components of cell membranes. Their accumulation fosters an immunosuppressive tumor microenvironment that supports cancer cell proliferation and metastasis.Moreover, lipid metabolism dysregulation within immune cells, particularly T cells, impairs immune surveillance and weakens the body's defenses against cancer. Abnormal lipid metabolism also contributes to drug resistance in PC. Despite these challenges, targeting lipid metabolism may offer a promising therapeutic strategy. By enhancing lipid peroxidation, the induction of ferroptosis-a form of regulated cell death-could impair the survival of PC cells and hinder disease progression.

Macrophages exhibit marked phenotypic heterogeneity within and across disease states, with lipid metabolic reprogramming contributing to macrophage activation and heterogeneity. Chronic inflammation has been observed in human benign prostatic hyperplasia (BPH) tissues, however macrophage activation states and their contributions to this hyperplastic disease have not been defined. We postulated that a shift in macrophage phenotypes with increasing prostate size could involve metabolic alterations resulting in prostatic epithelial or stromal hyperplasia.

Single-cell RNA-seq of CD45+ transition zone leukocytes from 10 large (>90 grams) and 10 small (<40 grams) human prostates was conducted. Macrophage subpopulations were defined using marker genes and evaluated by flow cytometry.

BPH macrophages do not distinctly categorize into M1 and M2 phenotypes. Instead, macrophages with neither polarization signature preferentially accumulate in large versus small prostates. Specifically, macrophage subpopulations with altered lipid metabolism pathways, demarcated by TREM2 and MARCO expression, accumulate with increased prostate volume. TREM2 high and MARCO high macrophage abundance positively correlates with patient body mass index and urinary symptom scores. TREM2high macrophages have a statistically significant increase in neutral lipid compared to TREM2low macrophages from BPH tissues. Lipid-rich macrophages were observed to localize within the stroma in BPH tissues. In vitro studies indicate that lipid-loaded macrophages increase prostate epithelial and stromal cell proliferation compared to control macrophages.

These data define two new BPH immune subpopulations, TREM2high and MARCOhigh macrophages, and suggest that lipid-rich macrophages may exacerbate lower urinary tract symptoms in patients with large prostates. Further investigation is needed to evaluate the therapeutic benefit of targeting these cells in BPH.

The role of the microbiome in prostate cancer is an emerging subject of research interest. Certain lifestyle factors, such as obesity and diet, can also impact the microbiome, which has been implicated in many diseases, such as heart disease and diabetes. However, this link has yet to be explored in detail in the context of prostate cancer. The purpose of this review is to explore the cross-talk between obesity, dietary interventions, and microbiome alterations in the development and progression of prostate cancer.

Many possible mechanisms exist linking obesity and dietary interventions to microbiome alterations and prostate cancer. The gut microbiome produces metabolites that could play a role in prostate cancer oncogenesis, including short-chain fatty acids, cholesterol derivatives, and folic acid. The microbiome also plays a pivotal role in the prostate tumor microenvironment (TME), contributing to inflammation, local tissue hypoxia, and epithelial-mesenchymal transition. A bidirectional relationship exists between obesity and the microbiome, and certain diets can enact changes to the microbiome, its associated metabolites, and prostate cancer outcomes.

Cross-talk exists between obesity, dietary interventions, and the role of the microbiome in the development and progression of prostate cancer. To further our understanding, future human studies in prostate cancer should investigate microbiome changes and incorporate an assessment of microbiome-derived metabolites and cellular/immune changes in the TME.

Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs)1,2, partly because there are immunosuppressive myeloid cells in tumours3,4. However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts (SPP1hi-TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8+ T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1hi-TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1hi-TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1hi-TAM-mediated immunosuppression in CD8+ T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1hi-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1hi-TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.

Macrophages undergo polarization, resulting in distinct phenotypes. These transitions, including de-/repolarization, lead to hysteresis, where cells retain genetic and epigenetic signatures of previous states, influencing macrophage function. We previously identified a set of interferon-stimulated genes (ISGs) associated with high lipid levels in macrophages that exhibited hysteresis following M1 polarization, suggesting potential alterations in lipid metabolism. In this study, we applied weighted gene co-expression network analysis (WGCNA) and conducted comparative analyses on 162 RNA-seq samples from de-/repolarized and lipid-loaded macrophages, followed by functional exploration. Our results demonstrate that during M1 hysteresis, the sustained high expression of Marco (SR-A6) enhances lipid uptake, while the suppression of Abca1/2 reduces lipid efflux, collectively leading to elevated intracellular lipid levels. This accumulation may compensate for reduced cholesterol biosynthesis and provide energy for sustained inflammatory responses and interferon signaling. Our findings elucidate the relationship between M1 hysteresis and lipid metabolism, contributing to understanding the underlying mechanisms of macrophage hysteresis.

Lipid accumulation has recently emerged as a key feature underlying the pro-tumorigenic role of macrophages. Here, we present a workflow to study macrophage lipid crosstalk with tumor cells. We describe steps for the identification, purification, and multi-omics characterization of lipid-laden macrophages (LLMs) from murine tumors and outline protocols to assess the functional significance of LLMs in cancer malignancy. This approach has the potential to uncover the source of lipids that drives LLM formation and its pro-tumorigenic potential in multiple cancer types. For complete details on the use and execution of this protocol, please refer to Kloosterman, Erbani, et al.1.

Pharmacological targeting of metabolic pathways represents an appealing strategy to selectively kill cancer cells while promoting antitumor functions of stromal cells. In this study, we assessed the effectiveness of 13 metabolic drugs (MDs) in steering in vitro generated breast tumor-educated macrophages (TEMs) toward an antitumoral phenotype. For that, the production of vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF-α), two important regulators of tumor progression, was evaluated. Notably, dichloroacetate (DCA), 6-aminonicotinamide (6-AN), and etomoxir decreased VEGF production and enhanced TNF-α release. Hence, we further clarified their impact on TEM metabolism using an untargeted NMR-based metabolomics approach. DCA downregulated glycolysis and enhanced the utilization of extracellular substrates like lactate while reconfiguring lipid metabolism. Several DCA-induced changes significantly correlated with heightened TNF-α production in response to pro-inflammatory stimulation. The inhibition of the pentose phosphate pathway by 6-AN was accompanied by enhanced glutaminolysis, which correlated with a decreased level of VEGF production. In etomoxir-treated TEM, inhibition of fatty acid oxidation was compensated through upregulation of glycolysis, catabolism of intracellular amino acids, and consumption of extracellular branched chain alpha-ketoacids (BCKA) and citrate. Overall, our results offer a comprehensive view of the metabolic signature of each MD in breast TEM and highlight putative correlations with phenotypic effects.

Gastric precancerous lesions (GPL), characterized by intestinal metaplasia and dysplasia, marks a pivotal juncture in the transformation from gastritis to gastric cancer. Research on GPL could offer fresh perspectives on preventing cancer occurrence.

This study employed 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) to establish GPL rat models and knocked BRD4 down in vivo to assess its impact on the lesions and macrophage morphology. Following that, the impacts of BRD4 knockdown on the malignant phenotypes of human gastric epithelial GES-1 cells were determined. Moreover, conditioned medium from macrophage was gathered and used for GES-1 cell culture. The involvement of macrophage polarization in the BRD4 regulatory mechanism in GES-1 cells was assessed.

This study elucidated that MNNG induced an increase level of BRD4 in the rat models. BRD4 knockdown reduced lesions based on pathological sections and immunohistochemistry to detect proliferative antigens. Western blotting and immunofluorescence showed that BRD4 knockdown suppressed epithelial-mesenchymal transition and macrophage M2 polarization. In in vitro experiments, BRD4 knockdown inhibited the malignant phenotype of GES-1 cells and the differentiation of THP-1 cells into M2 macrophages, respectively. The conditioned medium from M2 macrophages with BRD4 knockdown was co-incubated with GES-1 cells, which attenuated the malignant phenotypes compared with the medium from M2 macrophages.

Through in vivo and in vitro experiments, BRD4 upregulation was found to already occur during GPL, affecting macrophage polarization and epithelial cell cancerization. This finding provides an experimental basis for strategies targeting BRD4 inhibition at this critical stage.

NK cells are endowed with tumor killing ability, nevertheless most cancers impair NK cell functionality, and cell-based therapies have limited efficacy in solid tumors. How cancers render NK cell dysfunctional is unclear, and overcoming resistance is an important immune-therapeutic aim. Here, we identify autophagy as a central regulator of NK cell anti-tumor function. Analysis of differentially expressed genes in tumor-infiltrating versus non-tumor NK cells from our previously published scRNA-seq data of advanced human prostate cancer shows deregulation of the autophagic pathway in tumor-infiltrating NK cells. We confirm this by flow cytometry in patients and in diverse cancer models in mice. We further demonstrate that exposure of NK cells to cancer deregulates the autophagic process, decreases mitochondrial polarization and impairs effector functions. Mechanistically, CCAAT enhancer binding protein beta (C/EBPβ), downstream of CXCL12-CXCR4 interaction, acts as regulator of NK cell metabolism. Accordingly, inhibition of CXCR4 and C/EBPβ restores NK cell fitness. Finally, genetic and pharmacological activation of autophagy improves NK cell effector and cytotoxic functions, which enables tumour control by NK and CAR-NK cells. In conclusion, our study identifies autophagy as an intracellular checkpoint in NK cells and introduces autophagy regulation as an approach to strengthen NK-cell-based immunotherapies.

In continuously progressive tumor tissues, the causes of cellular stress are multiple: metabolic alterations, nutrient deprivation, chronic inflammation and hypoxia. To survive, tumor cells activate the stress response program, a highly conserved molecular reprogramming proposed to cope with challenges in a hostile environment. Not only cancer cells are affected, but stress responses in tumors also have a profound impact on their normal cellular counterparts: fibroblasts, endothelial cells and infiltrating immune cells. In recent years, there has been a growing interest in the interaction between cancer and immune cells, especially in difficult conditions of cellular stress. A growing literature indicates that knowledge of the molecular pathways activated in tumor and immune cells under stress conditions may offer new insights for possible therapeutic interventions. Counter-regulating the stress caused by the presence of a growing tumor can therefore be a weapon to limit disease progression. Here, we review the main pathways activated in cellular stress responses with a focus on immune cells present in the tumor microenvironment.

A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in murine macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cell lines, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in murine macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.

Invasion and metastasis are hallmarks of cancer. In addition to the well-recognized hematogenous and lymphatic pathways of metastasis, cancer cell dissemination can occur via the transcoelomic and perineural routes, which are typical of ovarian and pancreatic cancer, respectively. Macrophages are a universal major component of the tumor microenvironment and, in established tumors, promote growth and dissemination to secondary sites. Here, we review the role of tumor-associated macrophages (TAMs) in cancer cell dissemination and metastasis, emphasizing the diversity of myeloid cells in different tissue contexts (lungs, liver, brain, bone, peritoneal cavity, nerves). The generally used models of lung metastasis fail to capture the diversity of pathways and tissue microenvironments. A better understanding of TAM diversity in different tissue contexts may pave the way for tailored diagnostic and therapeutic approaches.

Cancer and metabolic disorders have emerged as major global health challenges, reaching epidemic levels in recent decades. Often viewed as separate issues, metabolic disorders are shown by mounting evidence to heighten cancer risk and incidence. The intricacies underlying this connection are still being unraveled and encompass a complex interplay between metabolites, cancer cells and immune cells within the tumour microenvironment (TME). Here, we outline the interplay between metabolic and immune cell dysfunction in the context of three highly prevalent metabolic disorders, namely obesity; two associated liver diseases, metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH); and type 2 diabetes. We focus primarily on macrophages and T cells, the critical roles of which in dictating inflammatory response and immune surveillance in metabolic disorder-associated cancers are widely reported. Moreover, considering the ever-increasing number of patients prescribed with metabolism disorder-altering drugs and diets in recent years, we discuss how these therapies modulate systemic and local immune phenotypes, consequently impacting cancer malignancy. Collectively, unraveling the determinants of metabolic disorder-associated immune landscape and their role in fuelling cancer malignancy will provide a framework essential to therapeutically address these highly prevalent diseases.

Lipid-associated macrophages (LAMs) are phagocytic cells with lipid-handling capacity identified in various metabolic derangements. During disease development, they locate to atherosclerotic plaques, adipose tissue (AT) of individuals with obesity, liver lesions in steatosis and steatohepatitis, and the intestinal lamina propria. LAMs can also emerge in the metabolically demanding microenvironment of certain tumors. In this review, we discuss major questions regarding LAM recruitment, differentiation, and self-renewal, and, ultimately, their acute and chronic functional impact on the development of metabolic diseases. Further studies need to clarify whether and under which circumstances LAMs drive disease progression or resolution and how their phenotype can be modulated to ameliorate metabolic disorders.

Prostate cancer is a malignant tumor of the male urological system with the highest incidence rate in the world, which seriously threatens the life and health of middle-aged and elderly men. The progression of prostate cancer involves the interaction between tumor cells and tumor microenvironment. Understanding the mechanisms of prostate cancer pathogenesis and disease progression is important to guide diagnosis and therapy. The emergence of single-cell RNA sequencing (scRNA-seq) and spatial transcriptome sequencing (ST-seq) technologies has brought breakthroughs in the study of prostate cancer. It makes up for the defects of traditional techniques such as fluorescence-activated cell sorting that are difficult to elucidate cell-specific gene expression. This review summarized the heterogeneity and functional changes of prostate cancer and tumor microenvironment revealed by scRNA-seq and ST-seq, aims to provide a reference for the optimal diagnosis and treatment of prostate cancer.

Reoperation is a treatment option for recurrent gliomas, yet factors impacting survival following reoperation remain poorly defined. Tumor immunity is profoundly associated with disease progression. Here, we analyze the immune status characteristics and their prognostic implications in recurrent gliomas.

Intratumoral and peripheral immune characteristics between primary and recurrent gliomas were compared by conducting immunohistological staining and hematological examination with our in-house samples, and analyzing bulk and single-cell sequencing data from publicly available sources. Survival analysis was conducted to identify immunological markers with prognostic significances.

We observed a significant reduction in peripheral lymphocyte count, while an elevation in neutrophil-to-lymphocyte ratio (NLR) and red cell distribution width-to-platelet ratio (RPR) in patients with recurrent gliomas than in newly-diagnosed patients. Higher NLR and RPR indicated worse survival following reoperation in recurrent patients. Transcriptomic and immunohistological analysis showed an increased infiltration of tumor-associated macrophages (TAMs) and CD8+ T cell in recurrent gliomas compared to primary gliomas in both IDH-wildtype and mutant subtypes. Moreover, the abundance of TAMs emerged as an independent indicator for an inferior prognosis in recurrent gliomas. Single-cell profiling revealed a significant heterogeneity in the phenotypes of TAMs between primary and recurrent gliomas. Notably, TAMs enriched in recurrent gliomas exhibited elevated expression of interferon-γ-induced genes, multiple immunosuppressive molecules (TGFB1, CD276), and increased activity in glycose and lipid metabolism, indicating metabolic reprogramming.

Recurrent gliomas demonstrate augmented immune cell infiltration, but they fail to overcome TAMs-induced immunosuppression. Immunosuppressive indices, including TAM abundance, peripheral NLR and RPR, have prognostic implications for recurrent gliomas.

Impaired fatty acid oxidation (FAO) and the therapeutic benefits of FAO restoration have been revealed in sepsis. However, the regulatory factors contributing to FAO dysfunction during sepsis remain inadequately clarified. In this study, we identified a subset of lipid-associated macrophages characterized by high expression of trigger receptor expressed on myeloid cells 2 (TREM2) and demonstrated that TREM2 acted as a suppressor of FAO to increase the susceptibility to sepsis. TREM2 expression was markedly upregulated in sepsis patients and correlated with the severity of sepsis. Knockout of TREM2 in macrophages improved the survival rate and reduced inflammation and organ injuries of sepsis mice. Notably, TREM2-deficient mice exhibited decreased triglyceride accumulation and an enhanced FAO rate. Further observations showed that the blockade of FAO substantially abolished the alleviated symptoms observed in TREM2-knockout mice. Mechanically, we demonstrated that TREM2 interacted with the phosphatase SHP1 to inhibit bruton tyrosine kinase-mediated (BTK-mediated) FAO in sepsis. Our findings expand the understanding of FAO dysfunction in sepsis and reveal TREM2 as a critical regulator of FAO that may provide a promising target for the clinical treatment of sepsis.

Prostate cancer (PCa) is a malignancy with significant immunosuppressive properties and limited immune activation. This immunosuppression is linked to reduced cytotoxic T cell activity, impaired antigen presentation, and elevated levels of immunosuppressive cytokines and immune checkpoint molecules. Studies demonstrate that cytotoxic CD8+ T cell infiltration correlates with improved survival, while increased regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are associated with worse outcomes and therapeutic resistance. Th1 cells are beneficial, whereas Th17 cells, producing interleukin-17 (IL-17), contribute to tumor progression. Tumor-associated neutrophils (TANs) and immune checkpoint molecules, such as PD-1/PD-L1 and T cell immunoglobulin-3 (TIM-3) are also linked to advanced stages of PCa. Chemotherapy holds promise in converting the "cold" tumor microenvironment (TME) to a "hot" one by depleting immunosuppressive cells and enhancing tumor immunogenicity.

This comprehensive review examines the immune microenvironment in PCa, focusing on the intricate interactions between immune and tumor cells in the TME. It highlights how TAMs, Tregs, cytotoxic T cells, and other immune cell types contribute to tumor progression or suppression and how PCa's low immunogenicity complicates immunotherapy.

The infiltration of cytotoxic CD8+ T cells and Th1 cells correlates with better outcomes, while elevated T regs and TAMs promote tumor growth, metastasis, and resistance. TANs and natural killer (NK) cells exhibit dual roles, with higher NK cell levels linked to better prognoses. Immune checkpoint molecules like PD-1, PD-L1, and TIM-3 are associated with advanced disease. Chemotherapy can improve tumor immunogenicity by depleting T regs and myeloid-derived suppressor cells, offering therapeutic promise.

Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the immune system is important in the pathogenesis and progression of numerous diseases, such as cancers, autoimmune diseases and metabolic diseases. The concept of immunometabolism was introduced over a decade ago to elucidate the intricate interplay between metabolism and immunity. The definition of immunometabolism has expanded from chronic low-grade inflammation in metabolic diseases to metabolic reprogramming of immune cells in various diseases. With immunometabolism being proposed and developed, the metabolic regulation of the immune system can be gradually summarized and becomes more and more clearer. In the context of many diseases including cancer, autoimmune diseases, metabolic diseases, and many other disease, metabolic reprogramming occurs in immune cells inducing proinflammatory or anti-inflammatory effects. The phenotypic and functional changes of immune cells caused by metabolic regulation further affect and development of diseases. Based on experimental results, targeting cellular metabolism of immune cells becomes a promising therapy. In this review, we focus on immune cells to introduce their metabolic pathways and metabolic reprogramming, and summarize how these metabolic pathways affect immune effects in the context of diseases. We thoroughly explore targets and treatments based on immunometabolism in existing studies. The challenges of translating experimental results into clinical applications in the field of immunometabolism are also summarized. We believe that a better understanding of immune regulation in health and diseases will improve the management of most diseases.

Metabolic changes play a crucial role in determining the status and function of macrophages, but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood. Here, we investigated the phenotype, contribution, and regulatory mechanisms of lipid droplet (LD)-laden macrophages (LLMs) in hepatocellular carcinoma (HCC). Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients. The LLMs displayed immunosuppressive phenotypes (with extensive expression of TREM2, PD-L1, CD206, and CD163) and attenuated the antitumor activities of CD8+ T cells. Mechanistically, tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages. LDs prolong LLM survival and promote CCL20 secretion, which further recruits CCR6+ Tregs to HCC tissue. Inhibiting LLM formation by targeting DGAT1 and DGAT2, which catalyze the synthesis of triglycerides, significantly reduced Treg recruitment, and delayed tumor growth in a mouse hepatic tumor model. Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.

Immunotherapy has shown promising therapeutic effects in hematological malignancies and certain solid tumors and has emerged as a critical and highly potential treatment modality for cancer. However, prostate cancer falls under the category of immune-resistant cold tumors, for which immunotherapy exhibits limited efficacy in patients with solid tumors. Thus, it is important to gain a deeper understanding of the tumor microenvironment in prostate cancer to facilitate immune system activation and overcome immune suppression to advance immunotherapy for prostate cancer. In this review, we discuss the immunosuppressive microenvironment of prostate cancer, which is characterized by the presence of few tumor-infiltrating lymphocytes, abundant immunosuppressive cells, low immunogenicity, and a noninflammatory phenotype, which significantly influences the efficacy of immunotherapy for prostate cancer. Immunotherapy is mainly achieved by activating the host immune system and overcoming immunosuppression. In this regard, we summarize the therapeutic advances in immune checkpoint blockade, immunogenic cell death, reversal of the immunosuppressive tumor microenvironment, tumor vaccines, immune adjuvants, chimeric antigen receptor T-cell therapy, and overcoming penetration barriers in prostate cancer, with the aim of providing novel research insights and approaches to enhance the effectiveness of immunotherapy for prostate cancer.

Cancer presents a significant global public health challenge. Within the tumor microenvironment (TME), macrophages are the most abundant immune cell population. Tumor-associated macrophages (TAMs) undergo metabolic reprogramming through influence of the TME; thus, by manipulating key metabolic pathways such as glucose, lipid, or amino acid metabolism, it may be possible to shift TAMs towards an antitumor state, enhancing the immune response against tumors. Here, we highlight the metabolic reprogramming of macrophages as a potential approach for cancer immunotherapy. We explore the major pathways involved in the metabolic reprogramming of TAMs and offer new and valuable insights on the current technologies utilized for TAM reprogramming, including genome editing, antibodies, small molecules, nanoparticles and other in situ editing strategies.

Tumors growing in metabolically challenged environments, such as glioblastoma in the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy their high energetic needs. To study the intricacies of this metabolic interplay, we interrogated the heterogeneity of the glioblastoma TME using single-cell and multi-omics analyses and identified metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their cholesterol accumulation, are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. Engulfment of cholesterol-rich myelin debris endows subsets of TAMs to acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression, thereby laying a framework to unveil targetable metabolic vulnerabilities in glioblastoma.

Cancer cells require a constant supply of lipids. Lipids are a diverse class of hydrophobic molecules that are essential for cellular homeostasis, growth and survival, and energy production. How tumors acquire lipids is under intensive investigation, as these mechanisms could provide attractive therapeutic targets for cancer. Cellular lipid metabolism is tightly regulated and responsive to environmental stimuli. Thus, lipid metabolism in cancer is heavily influenced by the tumor microenvironment. In this Review, we outline the mechanisms by which the tumor microenvironment determines the metabolic pathways used by tumors to acquire lipids. We also discuss emerging literature that reveals that lipid availability in the tumor microenvironment influences many metabolic pathways in cancers, including those not traditionally associated with lipid biology. Thus, metabolic changes instigated by the tumor microenvironment have 'ripple' effects throughout the densely interconnected metabolic network of cancer cells. Given the interconnectedness of tumor metabolism, we also discuss new tools and approaches to identify the lipid metabolic requirements of cancer cells in the tumor microenvironment and characterize how these requirements influence other aspects of tumor metabolism.