bims-flamet 2026-03-29 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2026–03–29
twenty papers selected by
Peio Azcoaga, Biodonostia HRI

The tumor microenvironment shapes gastric cancer progression by coordinating immune suppression and metabolic reprogramming.
The tumor microenvironment as a key regulator of radiotherapy response.
Regulation of Cancer Stem Cells in the Tumor Microenvironment.
The pivotal role of metabolism in shaping tumor-associated macrophages phenotype and function.
Targeting the chemokine-Treg axes in tumor immune evasion: from mechanisms to therapeutic opportunities.
Extracellular matrix stiffness in hepatocellular carcinoma: mechanisms and targeted therapeutic strategies.
Dual roles of immunosenescence in cancer immunotherapy.
Engineering the next generation of cellular therapies for solid tumors: multi-specific armored CARs and TME reprogramming strategies.
Tumorigenesis and Tumor Microenvironment in Lung Cancer.
TRIM21-mediated degradation of HILPDA overcomes anti-PD-1 immunotherapy resistance in breast cancer by limiting PD-L1 palmitoylation.
Exercise and CD8+ T cells: mechanisms of immune modulation in antitumor responses.
Lipid metabolic reprogramming of CD8+ T cells in the tumor microenvironment.
The Significance of CXCL1 in Cancer: An Overview of Molecular Mechanisms.
Research Progress on Anticancer Mechanism of Ginsenoside Regulating Tumor Microenvironment.
Mitochondrial Quality Control and Metabolic Reprogramming in Hepatocellular Carcinoma: Implications for Immunotherapy and Treatment Resistance.
Platelets induce VISTA expression and modulate the ovarian tumor microenvironment.
CX3CL1-CX3CR1 signaling orchestrates malignant progression of prostate cancer through luminal progenitor-macrophage crosstalk.
Ganglioside GM3 in the Tumor Microenvironment: Mechanisms of Signaling Regulation and Strategies for Angiogenesis Inhibition.
Cancer-associated fibroblast heterogeneity and its role in reshaping immunotherapy in solid cancers: potential strategies and clinical promise.
Tumor-Derived Exosomes Deliver Membrane-Bound Fgl2 to Activate FcγRIIB-Mediated Immunosuppression in Myeloid-Derived Suppressor Cells.

Front Immunol. 2026 ;17 1787060

The tumor microenvironment shapes gastric cancer progression by coordinating immune suppression and metabolic reprogramming.

Fuzhi Jiao, Zhen Wang, Jing Yuan, Fenglei Shi, Shengnan Zhang.

  Gastric cancer (GC) remains a leading cause of cancer mortality, largely owing to metastasis driven by a highly dynamic tumor microenvironment (TME). Immunosuppressive regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) orchestrate immune evasion through checkpoint signaling and polarization programs, while cancer-associated fibroblasts (CAFs) reshape stromal architecture and promote hypoxia. Concurrently, ECM remodeling-mediated by integrins, growth factors, and matrix metalloproteinases-activates oncogenic pathways such as PI3K/AKT/mTOR, MAPK/ERK, and TGF-β to drive dissemination. Metabolic reprogramming, including glycolysis-derived lactate accumulation, fatty acid and cholesterol dysregulation, and altered amino acid utilization, further constrain antitumor immunity and support angiogenesis and therapeutic resistance. This review summarizes recent advances in the bidirectional crosstalk between GC cells and key TME components, emphasizing how immune remodeling, extracellular matrix (ECM) reprogramming, and metabolic rewiring converge to sustain tumor progression, while highlighting integrative signaling networks linking immune cells, ECM, and metabolites, and providing emerging opportunities for multi-target strategies that disrupt TME-dependent metastasis.

Keywords:  extracellular matrix remodeling; gastric cancer; immune evasion; metabolic reprogramming; regulatory T cells; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2026.1787060
Front Immunol. 2026 ;17 1776636

The tumor microenvironment as a key regulator of radiotherapy response.

Xinchi Ma, Na Zhang.

  Radiotherapy (RT) remains a cornerstone of cancer treatment, yet its efficacy is often limited by tumor recurrence and resistance. Emerging evidence underscores the pivotal role of the tumor microenvironment (TME) in this process. RT-induced vascular damage exacerbates hypoxia, a key driver of resistance, while activation of cancer-associated fibroblasts promotes fibrosis and extracellular matrix remodeling that shield tumor cells. Furthermore, RT elicits a complex immune response, capable of both immunogenic cell death and fostering an immunosuppressive milieu enriched with regulatory T cells and myeloid-derived suppressor cells. We discuss the mechanisms through which these TME alterations, hypoxia, fibrotic signaling, and immune evasion, collectively contribute to RT resistance and recurrence. In this review, we summarize current knowledge on how RT remodels the TME, focusing on its dualistic impact on vascular integrity, stromal activation, and immune regulation. Finally, we outline the promising therapeutic strategies in overcoming TME-mediated resistance, including vascular normalization, targeting hypoxia-inducible factors, and combining RT with immunotherapies such as immune checkpoint blockade. Overall, a deeper understanding of TME dynamics post-RT is crucial for developing novel combination therapies to improve clinical outcomes.

Keywords:  VEGF; cancer; cancer-associated fibroblasts; combination therapy; hypoxia; immune suppression; radiotherapy resistance

DOI:  https://doi.org/10.3389/fimmu.2026.1776636
Cancer Heterog Plast. 2025 ;2(4):

Regulation of Cancer Stem Cells in the Tumor Microenvironment.

Aidan Li, Na Li, Yajing Yang, Linzhou Wang, Jessica Miao, Qi-En Wang.

  Cancer stem cells (CSCs) represent a subpopulation of cancer cells characterized by their capacity for self-renewal, differentiation, and tumorigenicity. CSCs exist along a spectrum of stemness regulated by both intrinsic factors and extrinsic signals from the tumor microenvironment (TME). The TME is composed of diverse cell types such as stromal and immune cells, and also physical factors such as the extracellular matrix and hypoxia. Environmental signals originating from the TME can induce non-CSCs to acquire stem-like traits, while CSCs in turn modulate the TME by recruiting and reprogramming immune and stromal cells. Analogous to normal stem cell niches, CSCs reside in or construct supportive niches that promote stemness, metastasis, immune evasion, and therapy resistance. This reciprocal interaction between CSCs and the TME underscores the complexity of cancer stemness and presents challenges and opportunities for therapeutics.

Keywords:  CSC niche; Cancer stem cells; cellular plasticity; tumor microenvironment

DOI:  https://doi.org/10.47248/chp2502040016
Int Immunopharmacol. 2026 Mar 23. pii: S1567-5769(26)00392-9. [Epub ahead of print]177 116547

The pivotal role of metabolism in shaping tumor-associated macrophages phenotype and function.

Mei Jun, Tiantian Li, Yilin Shi, Hang Yin, Wenjie Wu, Xinmin Dong, Xigetu He, Xiong Lai.

  Tumor progression is critically shaped by the dynamic interplay between tumor cells and the tumor microenvironment (TME). The TME harbors a diverse array of immune cells, encompassing T cell, B cell, NK cell and macrophages. Among these, TAMs profoundly shape tumor growth and metastasis by interacting with tumor cells and other immune cells. To adapt to the varied immune and metabolic cues in the TME, they undergo dynamic metabolic reprogramming, which recent advances have shown to involve extensive remodeling of glucose, lipid, and amino acid metabolism, along with the tricarboxylic acid cycle. However, critical knowledge gaps remain regarding the cellular heterogeneity of TAM metabolic reprogramming, divergent metabolic signatures across TAM subsets, and context-dependent variations in metabolic rewiring among different cancer types. However, the mechanisms by which these metabolic alterations translate into distinct functional phenotypes and shape the immune landscape of the TME remain poorly defined. This review systematically synthesizes the current knowledge on how metabolic remodeling in TAMs regulates their polarization and pro-tumor functions. We specifically focus on delineating the heterogeneity of TAM metabolic features across tumor types and subsets and discuss the implications of these metabolic variations for TAM-mediated immunosuppression. Furthermore, we summarize the representative therapeutic agents targeting key metabolic nodes in TAMs. By integrating emerging insights into TAM metabolism and associated pharmacologic interventions, this review aims to identify key unanswered questions and provide a theoretical framework for developing precision immunotherapies that target TAM metabolic nodes without compromising anti-tumor immunity.

Keywords:  Amino acid metabolism; Glucose metabolism; Lipid metabolism; Metabolic reprogramming; Tricarboxylic acid cycle; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.intimp.2026.116547
Front Immunol. 2026 ;17 1779388

Targeting the chemokine-Treg axes in tumor immune evasion: from mechanisms to therapeutic opportunities.

Chao Lian, Ling Liu, Xuanfen Zhang.

  Cancer immunotherapy has transformed oncology, yet its clinical efficacy is often limited by immune evasion within the tumor microenvironment (TME). Regulatory T cells (Tregs), a key immunosuppressive lineage, potently inhibit effector T-cell proliferation and activation, thereby dampening antitumor immune responses. Tregs are frequently enriched in diverse solid tumors, and their abundance correlates with poor prognosis, increased tumor invasiveness, and therapeutic resistance. A major mechanism driving this enrichment is the chemokine-chemokine receptor axis. Tumor cells, along with other stromal and immune cells in the TME, secrete chemokines including CCL22, CCL20, and CXCL12, which bind to CCR4, CCR6, and CXCR4 on Tregs and direct their recruitment and activation within the TME. This establishes an immunosuppressive niche that promotes tumor growth, facilitates metastasis, and reduces responsiveness to immunotherapy. This review consolidates eight experimentally validated chemokine-Treg axes from 2005 to 2025, with each study annotated by tumor type and represented by the highest observed level of evidence. A systematic representation illustrates how these axes mediate Treg-driven immunosuppression and maps their prevalence across cancers. Focusing on these axes provides mechanistic insights, highlights potential therapeutic targets, and identifies predictive biomarkers. Strategies targeting the chemokine-chemokine receptor axes, including selective receptor blockade, combination with immune checkpoint inhibitors, and omics-based approaches to resolve Treg heterogeneity, offer avenues to reprogram the immunosuppressive TME and enhance antitumor immunity.

Keywords:  cancer immunotherapy; chemokine receptors; chemokines; immune evasion; regulatory T cells; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1779388
Front Immunol. 2026 ;17 1773909

Extracellular matrix stiffness in hepatocellular carcinoma: mechanisms and targeted therapeutic strategies.

Zhuolin Zhou, Ximing Xu.

  Given the abundant stroma of the liver and that cirrhosis or hepatic fibrosis is the premalignant condition of most hepatocellular carcinomas (HCC), underscores the critical interaction between extracellular matrix (ECM) stiffness and the tumor microenvironment (TME) in the initiation, progression, and immunotherapy of HCC. This review presents a comprehensive exploration of the factors that regulate matrix stiffness, including the activation of cancer-associated fibroblasts (CAFs), the excessive deposition of ECM proteins, and cross-linking. Furthermore, this review explores the underlying molecular pathways through which matrix stiffness affects the prevalence of tumors and immune cells. Based on these premises, we delve into the potential targets and roles of pharmacological interventions targeting matrix stiffness in HCC and its immunotherapy, and highlight the considerable potential of biomaterials for the development of ECM stiffness-targeted agents. The potential exists for such agents to enhance the efficacy of immunotherapy and prolong the survival of patients diagnosed with HCC.

Keywords:  extracellular matrix stiffness; hepatocellular carcinoma; immunotherapy; pharmacological interventions; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1773909
Front Immunol. 2026 ;17 1779141

Dual roles of immunosenescence in cancer immunotherapy.

Ye Yu, Lei Sun, Jiawei Fan.

  Cellular senescence of tumor-infiltrating immune cells represents a hallmark of tumorigenesis, characterized by functional decline and severely compromised anti-tumor immunity. A growing body of evidence indicates that immunosenescence is not only a significant biological phenomenon within the tumor microenvironment (TME) but also serves as a therapeutic target with dual regulatory potential. Previous reviews have thoroughly examined the biomarkers associated with immunosenescence and its overarching impact on aging and disease. Nonetheless, comprehensive analyses of its specific and dual roles in cancer immunotherapy outcomes are still lacking. Consequently, a novel paradigm has been proposed for targeting immunosenescence: modulating the function of senescent immune cells may offer innovative cancer treatment strategies. This review synthesizes the bidirectional relationship between immune cell senescence and tumor progression, systematically examining the interactions between senescent immune cells and tumor advancement, and underscores the key molecular mechanisms driving immune senescence within the TME. By elucidating the characteristics and functions of immune cell senescence in tumor development and immune evasion, we aim to uncover new therapeutic perspectives and highlight potential targets for cancer immunotherapy.

Keywords:  TME (tumor microenvironment); cancer immunotherapy; immune cell; immunosenescence; senescence

DOI:  https://doi.org/10.3389/fimmu.2026.1779141
Clin Transl Oncol. 2026 Mar 21.

Engineering the next generation of cellular therapies for solid tumors: multi-specific armored CARs and TME reprogramming strategies.

Ling Mao, Lingfang Ding, Yunxia Ding.

  Chimeric antigen receptor (CAR) T-cell therapy has revolutionized hematologic oncology but remains largely ineffective against solid tumors, which evade immune attack through antigen heterogeneity, a suppressive tumor microenvironment (TME), and physical barriers. This review critically examines next-generation engineering strategies designed to overcome these formidable obstacles. We focus on the development of multi-specific and logic-gated CARs to prevent antigen escape and enhance precision, alongside "armored" constructs that secrete immunomodulatory payloads (e.g., cytokines, enzymes) or express dominant-negative receptors to reprogram the immunosuppressive stroma. Furthermore, we explore cooperative strategies that directly target and remodel the TME, including cancer-associated fibroblasts, the fibrotic extracellular matrix, abnormal vasculature, and suppressive myeloid cells. Early clinical signals are encouraging, but translation to solid tumors remains constrained by safety and manufacturing challenges and by limited predictive biomarkers. Here we synthesize advances in multispecific/logic-gated receptors, armored payloads, and TME-reprogramming strategies, highlighting translational priorities and pragmatic design principles for safer, manufacturable clinical candidates. Here, we argue that the most realistic path to meaningful clinical impact in solid tumors is a staged, biomarker-driven deployment of integrated platforms that (1) prioritize antigen breadth and safety in early clinical testing, (2) pair focused stromal remodeling with localized payload delivery, and (3) reserve the most complex synthetic circuits for settings where validated predictive biomarkers support risk-benefit tradeoffs.

Keywords:  Armored CARs; CAR-T cells; Immunotherapy; Solid tumors; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12094-026-04313-9
Curr Issues Mol Biol. 2026 Feb 26. pii: 247. [Epub ahead of print]48(3):

Tumorigenesis and Tumor Microenvironment in Lung Cancer.

Puneet Dhillon, Moshe Carroll, Haiying Cheng.

  Lung cancer remains a leading cause of cancer mortality worldwide and continues to impose substantial clinical and economic burdens. Beyond tumor-intrinsic oncogenic drivers, disease progression and therapy response are shaped by the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), endothelial cells, extracellular matrix, inflammatory mediators, etc. In lung cancer, chronic injury from tobacco smoke, airway disease, and treatment itself remodels local tissue programs that can either support antitumor immunity or promote immune exclusion, fibrosis, and metastatic seeding. Here, we analyze recent evidence linking lung tumorigenesis to TME ecology across histologies, with emphasis on CAF heterogeneity, spatial organization of immune niches, and the distinct microenvironments that govern organ-specific metastasis (including brain metastasis). We also evaluate emerging therapeutic strategies that aim to target or reprogram the TME, including perioperative immune checkpoint blockade, combined immunotherapy-radiotherapy approaches, and pathways such as IL-6 and TGF-β that coordinate immune suppression and stromal remodeling. Finally, we outline key gaps and potential future directions, such as longitudinal and spatial multi-omics, better biomarkers of stromal state, and trial designs that account for dynamic microenvironmental adaptation.

Keywords:  IL-6; TGF-β; brain metastasis; cancer-associated fibroblasts; immunotherapy; lung cancer; metastasis; perioperative therapy; tumor microenvironment

DOI:  https://doi.org/10.3390/cimb48030247
Oncogene. 2026 Mar 24.

TRIM21-mediated degradation of HILPDA overcomes anti-PD-1 immunotherapy resistance in breast cancer by limiting PD-L1 palmitoylation.

Xi Wang, Guangyan Li, Jiaming Wu, Baiyang Fu, Haoyang Zhang, Yichi Chen, Jianjiao Wang, Jianguo Zhang, Xi Chen.

Immune checkpoint blockade (ICB) targeting PD-1/PD-L1 improves outcomes across multiple malignancies, yet resistance to immune checkpoint blockade remains common. Here, we identify HILPDA as a tumor-intrinsic regulator of immune evasion in breast cancer. HILPDA overexpression increases the infiltration and suppressive activity of regulatory T cells while decreasing the infiltration, activation, and cytotoxicity of CD8+ T cells and natural killer cells, thereby establishing an immunosuppressive tumor microenvironment. Mechanistically, HILPDA binds to HSP90 and protects the transcription factor KLF5 from proteasomal degradation, sustaining fatty acid synthesis and lipid droplet accumulation. The resulting increase in palmitate augments PD-L1 palmitoylation at cysteine 272, enhancing PD-L1 membrane localization and palmitoylation-dependent stability and maintaining inhibitory signaling. We further showed that the E3 ligase TRIM21 mediates K63-linked polyubiquitination of HILPDA and promotes its degradation. In breast cancer models, pharmacologic engagement of TRIM21 with fenretinide decreases PD-L1 palmitoylation, reprograms the tumor microenvironment toward cytotoxic immunity, restores antitumor responses, and improves anti-PD-1 efficacy. Collectively, these results indicate that HILPDA-driven lipogenesis increases PD-L1 palmitoylation, leading to immune evasion and ICB resistance, and TRIM21/HILPDA-targeted combinations are proposed as a therapeutic strategy.

DOI: https://doi.org/10.1038/s41388-026-03728-6
J Mol Med (Berl). 2026 Mar 21. pii: 54. [Epub ahead of print]104(1):

Exercise and CD8+ T cells: mechanisms of immune modulation in antitumor responses.

Li Liu, Zhihao Deng, Ruiying Fang, Mi Zou, Junlin Ren, Yuan Gao, Jie Peng, Liang Hao.

  CD8+ T cells are the core effector cells of antitumor immunity. However, their functionality is vulnerable to metabolic stress within the tumor microenvironment (TME), and they experience significant inhibition from immunosuppressive signals, such as PD-1/PD-L1 and myeloid-derived suppressor cells (MDSC). This review explores how exercise enhances CD8+ T-cell antitumor efficacy through multidimensional synergistic mechanisms. At the molecular level, exercise stimulates the IL-15/IL-15Rα signaling pathway and triggers the release of myokines such as IL-6 and IL-7. These changes considerably boost CD8+ T-cell proliferation, viability, and granzyme B-dependent tumoricidal activity. Concurrently, exercise improves metabolic adaptation and sustains antitumor effects via metabolic reprogramming, which involves enhancing mitochondrial oxidative phosphorylation and increasing lactate-mediated stemness. Moreover, exercise optimizes TME vascular structure, downregulates PD-L1 expression, reduces MDSC proportion, and transforms the immunosuppressive environment, thus facilitating CD8+ T-cell infiltration and long-term function. Preclinical studies have verified that exercise works in tandem with immune checkpoint inhibitors, like anti-PD-1, to improve T-cell homing and counteract the depletion phenotype through the CXCR3-CXCL9/10 axis. Despite the positive progress, the mechanisms of exercise intensity, individual heterogeneity, and dynamic regulation of TME need to be explored in depth. Future studies need to combine multi-omics and dynamic immune monitoring to develop personalized exercise interventions based on CD8+ T-cell profiles. Exercise provides a low-cost, low-risk adjuvant strategy for cancer immunotherapy by targeting CD8+ T-cell function and TME remodeling, and its clinical translational potential needs large-scale validation.

Keywords:  CD8+ T cells; Exercise; Immunomodulation; Tumor; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00109-026-02659-9
Cell Signal. 2026 Mar 23. pii: S0898-6568(26)00148-8. [Epub ahead of print]143 112496

Lipid metabolic reprogramming of CD8+ T cells in the tumor microenvironment.

Lujing Mao, Juan Zou, Huimin Jin, Wenyan Liao, Yukun Li, Daichao Wu.

  Metabolic reprogramming within the tumor microenvironment is a critical driver of CD8+ T cell dysfunction that limits the efficacy of cancer immunotherapy. While glucose and amino acid deprivation are well-characterized, lipid metabolic rewiring has emerged as a fundamental determinant of T cell fate. This review systematically examines the mechanisms by which the tumor microenvironment disrupts CD8+ T cell lipid metabolism to promote functional exhaustion and ferroptosis. We first discuss how local stressors such as hypoxia and acidosis alongside systemic host factors including obesity and hyperlipidemia synergistically impose a metabolic siege on infiltrating T cells. We then detail the molecular pathways of dysregulation revealed by recent lipidomic profiling, including CD36-mediated uptake of oxidized lipids that drives ferroptosis, as well as the dysregulation of cholesterol homeostasis that impairs TCR signaling and induces endoplasmic reticulum stress via the IRE1α-XBP1 axis, which directly drives the transcriptional expression of immune checkpoints. Finally, we evaluate therapeutic strategies such as pharmacological modulation of lipid transporters and metabolic engineering of CAR-T cells which hold promise for restoring metabolic fitness and reinvigorating antitumor immunity.

Keywords:  CD8(+) T cells; Ferroptosis; Immunotherapy; Lipid metabolism; T cell exhaustion; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cellsig.2026.112496
Int J Mol Sci. 2026 Mar 16. pii: 2693. [Epub ahead of print]27(6):

The Significance of CXCL1 in Cancer: An Overview of Molecular Mechanisms.

Jan Korbecki, Mateusz Bosiacki, Edyta Dzięciołowska-Baran, Patrycja Pawlik, Michał Lubkowski, Ireneusz Walaszek, Katarzyna Barczak.

  Chemokine CXCL1, also known as Gro-α and MGSA, a ligand of CXCR2, is the best-known CXC chemokine in cancer processes, after CXCL8/IL-8 and CXCL12/SDF-1. This paper is the first review on the role of CXCL1 in general molecular processes associated with cancer. It provides a comprehensive overview that allows for an in-depth understanding of the importance of CXCL1 in tumor-related processes. In this review, however, we did not address the clinical aspects of CXCL1, as these were discussed in our previous review articles. The present paper focuses on the involvement of CXCL1 in cancer processes such as proliferation, cancer stem cell (CSC) function, senescence, angiogenesis, lymphangiogenesis, migration and metastasis, and effects on tumor-associated cells such as neutrophils, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), mesenchymal stem cells (MSCs), and cancer-associated fibroblasts (CAFs). It also describes the significance of CXCL1 in cancer-associated diseases such as cancer cachexia, cancer-associated immunodeficiency, neuroinflammatory-mediated affective-like behaviors, bone cancer pain, and acute kidney injury. We also present the effects of obesity on CXCL1-related cancer processes.

Keywords:  CXCL1; CXCR2; cancer; chemokine; inflammation; neutrophil; tumor

DOI:  https://doi.org/10.3390/ijms27062693
Curr Issues Mol Biol. 2026 Mar 20. pii: 329. [Epub ahead of print]48(3):

Research Progress on Anticancer Mechanism of Ginsenoside Regulating Tumor Microenvironment.

Tianjia Liu, Wei Li, Da Liu, Baiji Xue.

  Cancer is currently one of the most significant health threats facing humanity in general. The clinical treatment of cancer is constrained by the current development of chemotherapy drug resistance, poor pharmacokinetics, off-target toxicity, and insufficient intratumoral accumulation. Although surgery combined with chemotherapy is now maturely used in clinical practice, the results are unsatisfactory, and the incidence and mortality of cancer continue to increase year by year with high side effects from treatment. Therefore, it is important to find more effective therapeutic targets against cancer. Alterations in the tumor microenvironment can lead to cellular gene mutations, which are an important cause of tumorigenesis, and therapeutic interventions targeting the tumor microenvironment have been one of the most interesting research areas in the oncology community in recent years. Ginseng is rich in antitumor-active ingredients and is used in the treatment of many cancer diseases. Ginsenoside is one of the main active components of ginseng. This paper reviews the antitumor mechanism of action of ginsenoside through regulating the tumor microenvironment, emphasizing the key role of ginsenoside in the tumor microenvironment and providing a new target and theoretical basis for ginsenoside in the treatment of cancer.

Keywords:  cancer; ginsenoside; lipidosome; nano drug delivery system; tumor microenvironment

DOI:  https://doi.org/10.3390/cimb48030329
Cells. 2026 Mar 13. pii: 517. [Epub ahead of print]15(6):

Mitochondrial Quality Control and Metabolic Reprogramming in Hepatocellular Carcinoma: Implications for Immunotherapy and Treatment Resistance.

Yusra Zarlashat, Anna Picca.

  Hepatocellular carcinoma (HCC) is a leading cause of cancer death, characterized by poor prognosis in advanced stages despite available therapies. Dysfunctional mitochondrial can initiate both tumor progression and antitumor immunity. Altered mitochondrial quality control mechanisms, including dynamics, biogenesis, and degradation, contribute to mitochondrial decline supporting hepatocarcinogenesis and tumor survival. Within the immunosuppressive tumor microenvironment, HCC cells shift their metabolism toward glycolysis, which reduces nutrient availability and triggers mitochondrial dysfunction in infiltrating immune cells, leading to T-cell exhaustion and weakened cytotoxic activity. Herein, we discuss how immune checkpoint inhibitors may respond to this exhaustion. While most findings showing that these therapies partially restore mitochondrial bioenergetics in T cells have been conducted in preclinical studies, direct clinical evidence in HCC patients remains limited. By combining current knowledge on mitochondrial metabolism, immune escape, and treatment resistance, we discuss how targeting mitochondrial pathways may help improve immunotherapy responses and support new combination treatment approaches against HCC.

Keywords:  T-cell exhaustion; immune evasion; immunotherapy; metabolic reprogramming; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; tumor microenvironment

DOI:  https://doi.org/10.3390/cells15060517
Platelets. 2026 Dec 31. 37(1): 2644366

Platelets induce VISTA expression and modulate the ovarian tumor microenvironment.

Hani Lee, Brianne Sager, Anil Sood, Vahid Afshar-Kharghan, Min Soon Cho.

  Immune checkpoint regulators, such as the V-domain Ig suppressor of T cell activation (VISTA), play a critical role in shaping the tumor microenvironment (TME) and facilitating immune evasion. In ovarian cancer, VISTA exhibits more abundant and consistent expression than other immune checkpoints, including Programmed Death-Ligand 1 (PD-L1). This study examined the role of platelets in the regulation of VISTA in ovarian cancer using both in vitro and in vivo models. Our findings demonstrate that platelets upregulate VISTA expression in both myeloid and tumor cells, thereby promoting an immunosuppressive TME. Elevated VISTA levels were associated with higher platelet counts and poorer clinical outcomes. These results highlight that platelet-mediated VISTA upregulation is a potential therapeutic target for improving antitumor immune responses in ovarian cancer.

Keywords:  Immune checkpoint; neutrophils; ovarian cancer; platelet

DOI:  https://doi.org/10.1080/09537104.2026.2644366
Cell Oncol (Dordr). 2026 Mar 23. pii: 59. [Epub ahead of print]49(2):

CX3CL1-CX3CR1 signaling orchestrates malignant progression of prostate cancer through luminal progenitor-macrophage crosstalk.

Yu Jiang, Yuchen Guo, Lizhuang Han, Shiwei Wang, Fang Wang, Yongliang Zhao, Jiajia Wang, Junyan Han, Miaomiao Liu, Zhihua Liu, Qin Zhang.

   PURPOSE: Progression to castration-resistant prostate cancer (CRPC) is shaped by dynamic interactions within the tumor microenvironment (TME). However, the specific cellular crosstalk driving therapeutic resistance and metastasis remains incompletely defined. This study aims to identify key signaling axes between therapy-resistant luminal progenitor (luminal-2) cells and immune components in the TME, particularly tumor-associated macrophages (TAMs), and to determine how these interactions promote immunosuppression and cancer stem-like cell expansion during disease progression.
METHODS: We employed an integrative phenomics approach combining single-cell transcriptomics with genetically engineered mouse models (GEMMs) and orthotopic allograft models of prostate cancer. Spatiotemporal changes in cell populations were profiled across disease stages. The functional contribution of the CX3CL1-CX3CR1 axis was evaluated through genetic ablation of Cx3cr1 in host mice, followed by assessment of TAM infiltration, luminal progenitor cell dynamics, tumor growth, and immunosuppression signature score.
RESULTS: Single-cell profiling revealed a distinct luminal-2 progenitor population with high CX3CL1 expression that recruits CX3CR1+ TAMs and supports a pro-tumoral program. These CX3CL1hi luminal-2 cells and CX3CR1hi TAMs expand in a stage-specific manner and co-evolve during CRPC progression, forming an immunosuppressive and pro-metastatic niche. Host Cx3cr1 deletion disrupted this signaling axis, leading to reduced TAM infiltration, suppression of luminal progenitor cells expansion, and significant inhibition of tumor growth and progression.
CONCLUSION: The CX3CL1-CX3CR1 axis functions as a critical mediator of reciprocal signaling between luminal-2 progenitors and TAMs that promotes immune evasion, stemness maintenance, and therapeutic resistance in prostate cancer. Disrupting this pathway impairs the pro-tumoral niche and may represent a promising therapeutic approach for advanced prostate cancer.

Keywords:  CX3CL1-CX3CR1 axis; Luminal progenitor cells (luminal 2 cells); Prostate cancer; Tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.1007/s13402-026-01179-5
Biomolecules. 2026 03 19. pii: 464. [Epub ahead of print]16(3):

Ganglioside GM3 in the Tumor Microenvironment: Mechanisms of Signaling Regulation and Strategies for Angiogenesis Inhibition.

Min Zeng, Hongda Zhuang, Siyuan Zhao, Roger Chammas, Yong Chen.

  Ganglioside GM3, a fundamental glycosphingolipid on the mammalian cell surface, is a key regulator of transmembrane signaling and cellular recognition. In oncology, GM3 acts as a tumor suppressor by modulating the activity of various receptor tyrosine kinases (RTKs) and their downstream pathways. Recent studies highlight its function in the tumor microenvironment (TME), specifically its ability to impede pathological angiogenesis. This review summarizes the molecular mechanisms by which GM3 interferes with pro-angiogenic signaling, such as the VEGF/VEGFR axis, and discusses how this inhibition can be used for therapy. We explore the clinical potential of GM3-based strategies, including monoclonal antibodies and cancer vaccines, discussing the potential of targeting GM3 to reshape the TME and suppress tumor-associated vascularization.

Keywords:  HIF-1α; VEGF signaling; ganglioside GM3; targeted therapy; tumor angiogenesis; tumor microenvironment

DOI:  https://doi.org/10.3390/biom16030464
Front Cell Dev Biol. 2026 ;14 1761070

Cancer-associated fibroblast heterogeneity and its role in reshaping immunotherapy in solid cancers: potential strategies and clinical promise.

Peng Zu, Zhanwu Yu.

  Cancer-associated fibroblasts (CAFs) are important components of the solid tumour microenvironment (TME). CAFs have long been regarded as major promoters of the malignant progression of tumours and are widely recognized for their strong secretory activity and direct effect on the malignant ability of tumour cells. Recently, studies have found extensive crosstalk between CAFs and tumour immunity. CAFs constitute a highly heterogeneous group, and continuous studies have shown that their subpopulations have unique functions and can be widely involved in tumour immune regulation and immunotherapy. However, the specific mechanisms still need to be further revealed. In this paper, we focused on the interactions between CAFs subpopulations and immune cells in the TME and summarized the interactions between CAFs and immune cells from multiple perspectives to provide new insights for antitumour immunotherapy in solid tumours.

Keywords:  TME; cancer-associated fibroblast; heterogeneity; immunotherapy; solid cancers

DOI:  https://doi.org/10.3389/fcell.2026.1761070
Adv Sci (Weinh). 2026 Mar 24. e21784

Tumor-Derived Exosomes Deliver Membrane-Bound Fgl2 to Activate FcγRIIB-Mediated Immunosuppression in Myeloid-Derived Suppressor Cells.

Fenglin Lin, Dingqin Cai, Chunli Jian, Yaxian Qi, Linpeng Zheng, Qiao Yang, Longyao Zhang, Diangang Chen, Lingchen Li, Ping Cai, Lingyou Sun, Luping Zhang, Jianguo Sun.

  Myeloid-derived suppressor cells (MDSCs) play a pivotal role in establishing an immunosuppressive tumor microenvironment (TME), yet the mechanisms underlying their functional activation remain incompletely defined. Here, we identify the Fgl2-FcγRIIB signaling axis as a critical mediator of MDSC-driven immune evasion across solid tumors. Analysis of clinical specimens revealed that Fgl2 expression is significantly elevated in tumor tissues and inversely correlates with CD8+ T cell infiltration, while positively associating with the accumulation of FcγRIIB+ MDSCs and poor patient prognosis. We demonstrate that tumor-derived exosomes (TEX) function as efficient carriers that deliver membrane-bound Fgl2 (mFgl2) to MDSCs. These exosomes are internalized by MDSCs through FcγRIIB-mediated endocytosis, leading to an enhanced immunosuppressive function characterized by upregulated arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) expression and an increased capacity to suppress CD8+ T cell proliferation. Genetic ablation of FcγRIIB or antibody-mediated neutralization of Fgl2 abolished this exosome-mediated immunosuppressive programming, restoring T cell activity and impairing tumor growth in vivo. Importantly, a therapeutic strategy combining an exosome secretion inhibitor, in combination with PD-L1 blockade and MDSCs depletion, synergistically achieved potent antitumor effects. Our findings unveil a novel exosome-dependent mechanism through which tumors systemically educate MDSCs, establishing the Fgl2-FcγRIIB axis as a promising broad-spectrum target for cancer immunotherapy.

Keywords:  Fgl2‐FcγRIIB axis; MDSCs; TEX; TME; immunotherapy

DOI:  https://doi.org/10.1002/advs.202521784