bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2026–02–01
33 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. The Role of Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in the Tumor Microenvironment and Their Impact on Ovarian Cancer Survival and Therapy.
  2. Role of nanotechnology in modulating the tumor microenvironment to enhance immunotherapy efficacy.
  3. Lactylation and tumor immune regulation: insights from recent studies.
  4. Editorial: Tumor-host interactions: metabolic and signaling pathways altered in cancer, immune and stromal cells.
  5. Prominent protumoral cellular compartments of the tumor microenvironment in triple-negative breast cancer.
  6. Microbial Modulation: Unraveling the Influence of Gut Microbiota on Macrophage Polarization in Tumor Microenvironments.
  7. Cell death and immune escape in the tumor microenvironment: associated mechanisms, opportunities and challenges.
  8. Tumor Microenvironment in Cancer Biology: A Comprehensive Review of Stromal, Immune, and Vascular Components Driving Malignancy.
  9. Tumor-Associated Macrophages as Therapeutic Targets: Deciphering Interaction Networks and Advancing Clinical Translation.
  10. Mechanisms of Metabolic Reprogramming Regulating Immunosuppression in the Gastric Cancer Tumor Microenvironment.
  11. Multimodal profiling of CAR T cells against glioblastoma using a microengineered 3D tumor-on-a-chip model.
  12. Immunometabolic crosstalk between tumor- associated macrophages and ferroptotic cancer cells: mechanisms, regulation, and therapeutic applications.
  13. Unleashing CAR-T potential in solid tumors: overcoming intrinsic and extrinsic hurdles to improve therapy.
  14. The roles of the mtDNA-cGAS-STING axis in tumor immunity: from immune activation to immune evasion.
  15. Natural Products in Cancer Prevention and Therapy: Current Challenges and Future Directions.
  16. Natural products as metabolic modulators to enhance cancer immunotherapy: reprogramming the tumor microenvironment.
  17. MicroRNA-mediated modulation of cancer-associated fibroblasts in HER2-positive breast tumor microenvironment: a comprehensive review.
  18. Targeting lactic acidosis in the tumor microenvironment: Enhancing TACE efficacy in hepatocellular carcinoma.
  19. Immune cell metabolic reprogramming in hepatocellular carcinoma: mechanisms, tumor microenvironment, and future immunotherapeutic directions.
  20. The tumor ecosystem: Rewiring an open, systemically integrated network for therapeutic gain.
  21. Stem cell engineering for the generation of allogeneic CAR-directed natural killer T cells targeting endometrial carcinoma.
  22. Metadherin with Stromal-Immune Cues Drives CD36-Dependent Lipid Reprogramming and Metastasis in Triple-Negative Breast Cancer: Insights from a Hetero-Spheroid Model.
  23. Targeting sensory nerves in the tumor microenvironment: a new vulnerability in cancer therapy.
  24. Editorial: Immuno-metabolic interactions and cancer progression in the tumor microenvironment.
  25. Regulatory B Cells in Tumor Microenvironment.
  26. KRAS mutations reshape the immunosuppressive tumor microenvironment in triple-negative breast cancer: A novel perspective.
  27. Myeloid-derived suppressor cells promote therapy-induced resistance in prostate cancer.
  28. Lactylation in cancer: mechanistic insights, tumor microenvironment, and therapeutic horizons.
  29. Fibroblast-immune crosstalk in oral squamous cell carcinoma: from tumor promotion to immune evasion.
  30. CAR-T cell immunotherapy of malignant melanoma.
  31. Cancer-Associated Fibroblasts in Prostate Cancer: Unraveling Mechanisms and Therapeutic Implications.
  32. TGF-β in tumor development and progression: mechanisms and therapeutics.
  33. Decoding the mechanical language of the tumor microenvironment: From physical forces to malignant behaviors.
  1. Curr Oncol. 2026 Jan 19. pii: 59. [Epub ahead of print]33(1):
    The Role of Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in the Tumor Microenvironment and Their Impact on Ovarian Cancer Survival and Therapy.
    Alena A McQuarter, Joseph Cruz, Celina R Yamauchi, Mariem Chouchen, Cody S Carter, Tonya J Webb, Salma Khan.
      Ovarian cancer is the deadliest gynecologic cancer, mainly because it is often diagnosed late and resists standard treatments. The tumor microenvironment (TME) plays a major role in disease progression and therapy failure. Two key components of the TME, cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), create conditions that facilitate tumor growth and immune evasion. CAFs are highly diverse and originate from sources like fibroblasts and stem cells. They support cancer by remodeling the extracellular matrix, promoting angiogenesis, and releasing cytokines and growth factors that aid tumor survival. TAMs, which are usually in an M2 state, also promote metastasis and suppress immune responses by secreting immunosuppressive molecules. Together, CAFs and TAMs interact with cancer cells to activate pathways such as the TGF-β, IL-6, and PI3K/AKT pathways, which drive resistance to therapy. New treatments aim to block these interactions by targeting CAFs and TAMs through depletion, reprogramming, or pathway inhibition, often combined with immunotherapy. Advances such as single-cell sequencing and spatial transcriptomics now enable more precise identification of CAF and TAM subtypes, enabling more targeted therapies. This review summarizes their roles in epithelial ovarian cancer and explores how targeting these cells could improve outcomes.
    Keywords:  cancer-associated fibroblasts; epithelial ovarian cancer; extracellular matrix; single-cell sequencing; stromal remodeling; targeted therapies; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/curroncol33010059
  2. World J Clin Oncol. 2026 Jan 24. 17(1): 111294
    Role of nanotechnology in modulating the tumor microenvironment to enhance immunotherapy efficacy.
    Ayushi Jain, Saloni Verma, Alisha Jadhav, Sharon John, Shalini Gupta.
      The immunosuppressive tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is marked by hypoxia, acidity, and abundant stromal cells, such as cancer-associated fibroblasts, tumor-associated macrophages, and myeloid-derived suppressor cells, along with factors such as tobacco and alcohol exposure, human papillomavirus infection, and microbial imbalance that drive immune evasion and poor immunotherapy responses. This review critically evaluated nanotechnology-driven strategies for reprogramming the OSCC TME, focusing on overcoming immunosuppression, hypoxia, stromal barriers, and OSCC-specific challenges to enhance immunotherapy outcomes. Personalized nanotherapies guided by TME profiling, combination with radiotherapy/chemotherapy, and theranostic nanoparticles show promise despite manufacturing/regulatory challenges. Nanotechnology enables transformative TME reprogramming to potentiate OSCC immunotherapy, necessitating interdisciplinary research and clinical validation.
    Keywords:  Hypoxia; Immunotherapy; Nanomedicine; Nanoparticles; Oral squamous cell carcinoma; Tumor associated macrophages; Tumor microenvironment
    DOI:  https://doi.org/10.5306/wjco.v17.i1.111294
  3. Front Immunol. 2025 ;16 1699314
    Lactylation and tumor immune regulation: insights from recent studies.
    Chunhong Li, Xiulin Jiang, Yixiao Yuan, Qiang Wang.
      Lactate, a major product of glycolysis, accumulates abundantly in the tumor microenvironment (TME), serving not only as a hallmark of metabolic dysregulation but also as a key driver of immunosuppression. In recent years, lysine lactylation (Kla), a novel post-translational modification (PTM), has been identified, linking lactate metabolism closely with epigenetic regulation. Current studies indicate that lactylation modulates gene transcription and metabolic pathways in tumor cells while broadly influencing immune cell functions. For example, histone lactylation in macrophages promotes M2 polarization, enhancing immunosuppressive phenotypes; T cells, natural killer (NK) cells, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs) may also be regulated by lactylation, thereby affecting anti-tumor immune responses and the efficacy of immune checkpoint inhibitors. As the mechanistic understanding of lactylation deepens, its roles in tumor immune evasion and therapy resistance are becoming increasingly evident. Targeting lactate metabolism and lactylation-related enzymatic processes, potentially in combination with immunotherapy, may represent a promising therapeutic strategy. This mini-review summarizes recent advances in lactylation research in tumor immunity and discusses its potential clinical implications and future directions.
    Keywords:  immune evasion; immunotherapy; lactylation; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1699314
  4. Front Mol Biosci. 2026 ;13 1778371
    Editorial: Tumor-host interactions: metabolic and signaling pathways altered in cancer, immune and stromal cells.
    Joanna Kopecka, Valentina Audrito.
      
    Keywords:  TME; cancer cells; immune cells; stromal cells; tumor microenvironment; tumor progression; tumor-host crosstalk
    DOI:  https://doi.org/10.3389/fmolb.2026.1778371
  5. Front Cell Dev Biol. 2025 ;13 1668583
    Prominent protumoral cellular compartments of the tumor microenvironment in triple-negative breast cancer.
    Shuai Sun, Pan Zhao, Changrong Wang, Junjun Du, Tingting Zhang, Xiangyun He, Zhibo Zuo, Nan Li, Rongjing Zhou.
      Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by the absence of estrogen, progesterone, and HER2 receptor expression. This malignancy is often associated with a poor prognosis, early recurrence, and limited treatment options. The tumor microenvironment (TME) in TNBC plays a pivotal role in tumor progression, immune evasion, and therapeutic resistance. In recent years, an increasing body of evidence has highlighted the critical interactions between cancer cells and the components within the TME, including immune cells and soluble components. These interactions influence not only the biological behavior of the tumor but also its response to treatment. Exploring the complex interplay between tumor cells and immune components continues to inform the development of more effective therapeutic approaches. In this study, we provide a synopsis of advancements regarding the TME in TNBC. In light of different cellular compartments, we delineate multiscale interplays within the stroma-tumor symbiosis and highlight their antitumor functions and promising targeting strategies.
    Keywords:  chemotherapy; drug resistance; immunotherapy; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2025.1668583
  6. Cells. 2026 Jan 12. pii: 136. [Epub ahead of print]15(2):
    Microbial Modulation: Unraveling the Influence of Gut Microbiota on Macrophage Polarization in Tumor Microenvironments.
    Jonathan Trejo, Hayes Koegeboehn, Farah Faizuddin, Ryan Logan, Michel Toutoungy, Aadil Sheikh, Tamer E Fandy, Sergio Saucedo, Victor M Vasquez, Thien Nguyen, Jennifer T Grier, Ghislaine Mayer, Jessica Chacon.
      The intricate interplay between the human microbiota and the immune system has garnered significant attention in recent years, particularly concerning its implications in cancer biology. Macrophages, pivotal players in the tumor microenvironment (TME), exhibit diverse phenotypes that can either promote tumor progression or inhibit it. This review explores the multifaceted role of the microbiota in modulating macrophage polarization within the TME. We highlight recent findings that demonstrate how specific microbial communities influence macrophage behavior through metabolic pathways, immune signaling, and epigenetic modifications. Furthermore, we discuss the therapeutic potential of manipulating the microbiota to reprogram macrophage phenotypes, thereby enhancing antitumor immunity. By integrating insights from microbiology, immunology, and oncology, this article aims to provide a comprehensive overview of the microbiota's impact on macrophage dynamics in cancer, paving the way for innovative therapeutic strategies that harness this relationship for improved clinical outcomes.
    Keywords:  cancer immunotherapy; gut microbiota; macrophage polarization; microbial metabolites; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/cells15020136
  7. Apoptosis. 2026 Jan 28. 31(2): 59
    Cell death and immune escape in the tumor microenvironment: associated mechanisms, opportunities and challenges.
    Jincai Guo, Ya Liu, Ying Huang, Xiang Liu, Yixiang Hu.
      The tumor microenvironment (TME) is a dynamic and complex biological system composed of cancer cells, stromal cells, fibroblasts, immune cells, extracellular matrix, and tumor vasculature. It plays a pivotal role in tumor initiation, progression, invasion, and metastasis, and therapeutic strategies targeting the TME have opened new avenues for tumor treatment and management. Within the TME, immune cells directly influence tumor development, while tumor cells evade immune surveillance through the regulation or silencing of key genes. Growing evidence suggests that cell death mechanisms are central to both tumorigenesis and immune evasion, providing targets for the development of diverse therapeutic strategies. This review explores the intricate relationship between various forms of cell death and immune escape in tumor cells, examining potential regulatory mechanisms of the TME in tumor progression from a micro perspective. Furthermore, it discusses the clinical applications of tumor immune escape and cell death mechanism-related targets and treatment strategies in antitumor immunity.
    Keywords:  Cancer; Cell death; Immune escape; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10495-026-02257-7
  8. Cureus. 2025 Dec;17(12): e100320
    Tumor Microenvironment in Cancer Biology: A Comprehensive Review of Stromal, Immune, and Vascular Components Driving Malignancy.
    Sushma T A, Sudarshan Gupta, Priyanka Kiyawat, Yashodha Darshan, Kumar Sambhav, Saiyad Shabbirali Shamshadali.
      The tumor microenvironment (TME), comprising the extracellular matrix (ECM), stromal cells, immune cells, and vascular components, plays a decisive role in cancer growth, metastasis, and treatment response. Although cancer research has traditionally focused on tumor cells, increasing evidence shows that the TME actively influences tumor behavior. This narrative review synthesizes recent findings on the stromal, immune, and vascular elements of the TME, drawing on advanced approaches such as single-cell RNA sequencing and AI-assisted imaging. Cancer-associated fibroblasts (CAFs) promote tumor progression through ECM remodeling and immune suppression, while vascular abnormalities limit drug delivery and contribute to therapeutic resistance. Emerging TME-targeted strategies, including anti-angiogenic agents, immune checkpoint inhibitors, and stromal-directed therapies, show promise but remain challenged by TME heterogeneity and tumor adaptability. The evidence indicates that targeting the TME represents a major shift in cancer therapy and offers important opportunities to develop more effective and personalized treatment strategies.
    Keywords:  angiogenesis; extracellular matrix; immune evasion; stromal cells; tumor microenvironment
    DOI:  https://doi.org/10.7759/cureus.100320
  9. MedComm (2020). 2026 Feb;7(2): e70599
    Tumor-Associated Macrophages as Therapeutic Targets: Deciphering Interaction Networks and Advancing Clinical Translation.
    Wurihan Bao, Xiaojie Qu, Yiqi Wang, Dan Huang, Huiling Zhang, Mingyuan Dong, Han Sun, Zhaogang Yang, Xuefeng Li.
      Tumor-associated macrophages (TAMs) represent the most abundant immune cell population within the tumor microenvironment and are central drivers of malignant progression and treatment resistance. High TAMs infiltration in solid tumors consistently correlates with poor clinical outcomes, largely due to their role in establishing an immunosuppressive milieu that supports tumor growth, metastasis, and undermines the efficacy of chemotherapy, radiotherapy (RT), and immune checkpoint inhibitors. Although TAMs are well-recognized promoters of tumor progression, the development of effective strategies to therapeutically target them remains an unmet clinical need. In this review, we examine the multifaceted mechanisms through which TAMs contribute to malignancy, including phagocytic signaling modulation, metabolic reprogramming, exosomal communication, and crosstalk with other immune cells. We also evaluate three key therapeutic strategies: blocking TAMs recruitment and survival, reprogramming TAMs toward antitumor phenotypes, and the emerging approach of chimeric antigen receptor macrophage therapy. Furthermore, we highlight the synergistic potential of integrating TAMs-targeted strategies with conventional chemotherapy, RT, and immunotherapeutic approaches. By synthesizing current clinical evidence, this review aims to inform the rational design of next-generation TAMs-targeted interventions and to propose novel strategies for overcoming treatment resistance.
    Keywords:  immune escape; immunotherapy; tumor microenvironment; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/mco2.70599
  10. Biomolecules. 2026 Jan 16. pii: 160. [Epub ahead of print]16(1):
    Mechanisms of Metabolic Reprogramming Regulating Immunosuppression in the Gastric Cancer Tumor Microenvironment.
    Wenting Dong, Xuepeng Qian, Honglin Liu, Jinhai Huo, Weiming Wang.
      Immunotherapy, especially immune checkpoint inhibitors (ICIs), has become one of the core therapeutic approaches in cancer in recent years. It demonstrates remarkable efficacy in the treatment of melanoma and lung cancer. Conversely, its use in treating gastric cancer (GC) is not associated with considerable benefits. The high heterogeneity of GC and the tumor microenvironment (TME) may directly influence this phenomenon. This review focuses on the correlation between Helicobacter pylori (H. pylori) infection, gastric physiology, and molecular subtype-specific induction pathways, with emphasis on the unique metabolic features of GC. It explores the connection of H. pylori infection, gastric physiologic functions, and molecular subtype-specific induction mechanism of GC with the special metabolism of GC. It also explains the relationship between immune metabolic reprogramming and the suppressive TME in GC. Crucially, we summarize emerging therapeutic strategies targeting metabolic vulnerabilities. Furthermore, we explore the potential of subtype-guided metabolic therapies to overcome the challenges of the immunosuppressive tumor microenvironment in GC.
    Keywords:  Helicobacter pylori; gastric cancer; immune microenvironment; metabolic reprogramming; molecular subtypes; therapeutic strategies
    DOI:  https://doi.org/10.3390/biom16010160
  11. Bioact Mater. 2026 May;59 724-744
    Multimodal profiling of CAR T cells against glioblastoma using a microengineered 3D tumor-on-a-chip model.
    Kalpana Ravi, Shannon Trottier, Obed B Amissah, Grace C Russell, Daniel Rho, Gloria B Kim, Mehdi Nikkhah.
      Immunotherapies such as chimeric antigen receptor (CAR) T cells have shown promising outcomes in hematological cancer but face challenges in targeting solid tumors like glioblastoma (GBM). Advancing this therapy for GBM has been hindered by the lack of preclinical tools that accurately model the complex interplay between CAR T cells and tumor cells within the tumor microenvironment (TME) - interactions critical for optimizing CAR constructs and improving efficacy. Physiologically relevant models that closely mimic the solid TME are therefore highly sought after in developing CAR T therapies. Here, we report a microengineered glioblastoma-on-a-chip (GOC) model with a functional vascular network to investigate the efficacy and selectivity of IL-13 mutein CAR T cells (TV-13) against U87 GBM tumor cells expressing high interleukin-13 receptor alpha-2 (IL13Rα2), compared with the ubiquitously expressed IL13Rα1. This biomimetic platform recapitulates the GBM TME and enables dynamic evaluation of CAR T cell responses under locoregional administration, paralleling clinical approaches. Using the organotypic GOC model, we evaluated CAR T cell-mediated inhibition of GBM invasion, monitored real-time dynamic CAR T-U87 interactions, and quantified the release of cytotoxic, proinflammatory, and stimulation-associated cytokines as measures of T cell effector function. CAR T cells induced a density-dependent reduction in U87 migration, accompanied by robust cytokine release, while TV-13 maintained specificity towards IL13Rα2 tumor antigen over IL13Rα1. Additionally, we further demonstrated the efficacy of CAR T cells against patient-derived GBM cells within the GOC model. Collectively, these findings highlight the GOC platform as a powerful preclinical screening tool for cancer immunotherapy optimization.
    Keywords:  CAR T cells; Cancer immunotherapy; IL13Rα2; Microfluidics; T cell engineering; Tumor-on-a-chip (TOC)
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.01.003
  12. Front Immunol. 2025 ;16 1628142
    Immunometabolic crosstalk between tumor- associated macrophages and ferroptotic cancer cells: mechanisms, regulation, and therapeutic applications.
    Zixing Qian, Zhuo Zhang, Wei Bai, Jiaxuan Li, Xianjun Rao, Guodong Huang, Jiabao Liu, Wei Wei.
      Tumor-associated macrophages (TAMs) are central regulators of the metabolic and immunological landscape of solid tumors and are increasingly recognized as key determinants of cancer-cell susceptibility to ferroptosis. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, is tightly shaped by metabolic cues within the tumor microenvironment (TME). TAMs, through their remarkable metabolic plasticity, modulate iron flux, redox balance, polyunsaturated fatty-acid (PUFA) availability, and glutathione-dependent antioxidant pathways, each of which directly influences ferroptotic vulnerability in neighboring tumor cells. In this review, we synthesize current evidence linking TAM polarization states to the regulation of ferroptosis-related processes, including lipid remodeling, cystokine metabolism, reactive oxygen species (ROS) buffering, and immunometabolic signaling. We further discuss how TAM-derived cytokines, lipid mediators, and iron-handling proteins orchestrate a microenvironment that either promotes or restrains ferroptotic cell death. Finally, we highlight emerging therapeutic strategies aimed at rewiring TAM metabolism or exploiting ferroptosis to overcome immune suppression and therapy resistance. By integrating immunological and metabolic dimensions, this review provides a framework for understanding TAM-ferroptosis crosstalk and its implications for precision immunotherapy in cancer.
    Keywords:  cancer therapy; ferroptosis; immunometabolism; iron homeostasis; redox signaling; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1628142
  13. Cancer Immunol Immunother. 2026 Jan 27. 75(2): 37
    Unleashing CAR-T potential in solid tumors: overcoming intrinsic and extrinsic hurdles to improve therapy.
    Zhiwei Zhang, Dawei Cui, Hao Wang, Liming Wu, Xia Liu.
      Chimeric antigen receptor (CAR) T cell therapy has shown transformative success in hematologic malignancies, yet its application in solid tumors remains limited by a combination of intrinsic and extrinsic barriers. Intrinsically, CAR-T cells face challenges such as CAR instability, T cell exhaustion, insufficient tumor infiltration, and poor persistence. Extrinsically, the tumor microenvironment (TME) acts as a formidable obstacle, with physical barriers, metabolic constraints, and immunosuppressive signals that dampen CAR-T cell function. Recent advancements in CAR transduction, genetic reprogramming, and combination therapies have revealed novel strategies to overcome these hurdles. This review explores cutting-edge innovations aimed at unleashing the full potential of CAR-T therapy in solid tumors, focusing on strategies that enhance CAR-T cell function and persistence while addressing the immunosuppressive TME. By examining both intrinsic and extrinsic factors, we provide a comprehensive framework for future research and clinical application to improve CAR-T therapy for solid tumor treatment.
    Keywords:  CAR transduction; CAR-T cell; Combination therapy; Solid tumor; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00262-025-04278-8
  14. Front Immunol. 2025 ;16 1739559
    The roles of the mtDNA-cGAS-STING axis in tumor immunity: from immune activation to immune evasion.
    Nan Huang, Zheng Liu, Haibo Lei, Xiang Liu.
      In the tumor microenvironment (TME), stress-induced mitochondrial DNA (mtDNA) leakage activates the mtDNA-cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) axis, which exerts a "double-edged sword" role in tumor immunity. On the one hand, it activates the STING- interferon regulatory factor 3 (IRF3) pathway via cyclic GMP-AMP (cGAMP) synthesis by cGAS, induces type I interferons (IFN-I), enhances the cytotoxic functions of CD8+ T cells and natural killer (NK) cells as well as the antigen-presenting capacity of dendritic cells (DCs), and also promotes M1 macrophage polarization and neutrophil extracellular trap (NETs) formation, thereby driving immune activation. On the other hand, sustained activation of this axis can induce programmed cell death ligand 1 (PD-L1) expression, recruit myeloid-derived suppressor cells (MDSCs), and cause T cells exhaustion, facilitating tumor immune evasion. Targeting mtDNA stability, constructing nano-drug delivery systems, or combining with immune checkpoint blockade can reshape the tumor immune microenvironment and provide new ideas for precision immunotherapy. This article systematically summarizes the dual effects of this axis on the tumor immune microenvironment, which not only deepens the understanding of cancer immunology but also provides guidance for the research, development, and optimization of precision tumor immunotherapies, and is expected to improve patient prognosis.
    Keywords:  immune activation; immune evasion; mtDNA-cGAS-STING; tumor immune microenvironment; tumor therapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1739559
  15. MedComm (2020). 2026 Feb;7(2): e70585
    Natural Products in Cancer Prevention and Therapy: Current Challenges and Future Directions.
    Ruimiao Qian, Jun Ge, Ni Fan, Zheng Sun, Chengcheng Zhao, Yujiao Sun, Yingpeng Li, Yunfei Li, Hui Fu.
      Natural products, originating from diverse biological sources, serve as a critical reservoir of bioactive compounds for cancer intervention across prevention, treatment, and supportive care. Their mechanisms extend beyond direct cytotoxicity to include modulation of tumor metabolism-such as glucose, lipid, and glutamine pathways-and the tumor microenvironment (TME), highlighting their multifaceted role in oncology. However, a systematic synthesis of how natural products concurrently target metabolic reprogramming and immune-stromal components across different clinical phases remains lacking. This review delineates the therapeutic applications of natural products-such as flavonoids, alkaloids, and terpenoids-across the clinical continuum, including perioperative support, concurrent chemoradiotherapy, maintenance therapy, and metastasis suppression. We detail their actions in disrupting core metabolic pathways and elucidate their influence on TME components like cancer-associated fibroblasts, extracellular matrix, and immune cells including tumor-associated macrophages and T lymphocytes. Furthermore, we discuss innovative delivery strategies-including nanocarriers and codelivery systems-that enhance bioavailability and enable synergistic combination with chemotherapy or immunotherapy. By integrating mechanistic insights with clinical translation strategies, this work provides a comprehensive framework for employing natural products in biomarker-driven, precision oncology regimens, supporting their evolving role in multimodal cancer care.
    Keywords:  cancer metabolic reprogramming; immune modulation; natural products; precision medicine; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.70585
  16. Front Immunol. 2025 ;16 1740644
    Natural products as metabolic modulators to enhance cancer immunotherapy: reprogramming the tumor microenvironment.
    Xiaoyu Fan, Shushu Guo, Wanfang Li, Yingyin Wang, Jie Bao, Jiuming He, Hongtao Jin.
      Cancer remains a major global health challenge, and although immunotherapy has achieved remarkable breakthroughs, its efficacy is often limited by tumor-induced immunosuppression within the tumor microenvironment (TME). Emerging evidence indicates that metabolic reprogramming plays a pivotal role in shaping the TME and regulating antitumor immune responses. Targeting tumor and immune cell metabolism has therefore become a promising strategy to enhance the effectiveness of cancer immunotherapy. This review first summarizes the metabolic reprogramming that occurs within the TME, including alterations in glucose, lipid, and amino acid metabolism in tumor cells, as well as the metabolic adaptation of immune cells. We then highlight recent advances in natural products that modulate key metabolic pathways and their potential to reshape the immunosuppressive TME. Special emphasis is placed on natural compounds that not only inhibit tumor cell metabolism but also restore the metabolic fitness of immune cells, thereby improving antitumor immunity. In addition, advances in delivery strategies, including nanocarrier-based and stimuli-responsive systems, are reviewed for their roles in improving the bioavailability, stability, and tumor targeting of natural metabolism-regulating agents. Finally, we discuss the current status and challenges of translating natural metabolism-regulating agents into clinical applications, including issues of dose optimization, safety evaluation, and patient selection. Despite these hurdles, precision targeting of metabolic pathways, interdisciplinary collaboration, and the discovery of novel compounds-particularly immune-sensitizing agents derived from traditional medicine-are expected to accelerate progress. Collectively, natural products represent promising adjuvant strategies for cancer immunotherapy, with great potential to overcome current therapeutic limitations and improve clinical outcomes.
    Keywords:  cancer immunotherapy; immune metabolism regulation; metabolic reprogramming; natural products; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1740644
  17. Discov Oncol. 2026 Jan 28.
    MicroRNA-mediated modulation of cancer-associated fibroblasts in HER2-positive breast tumor microenvironment: a comprehensive review.
    Mustafa T Ardah, Waleed K Abdulsahib, Hasanain Amer Naji, S Renuka Jyothi, Samir Sahoo, J Bethanney Janney, Vipasha Sharma, Aashna Sinha, Mohigul Kholiyeva.
      The intricate interplay within the tumor microenvironment (TME) significantly dictates the trajectory of cancer progression and therapeutic response. In HER2-positive breast cancer, a particularly aggressive subtype, cancer-associated fibroblasts (CAFs) emerge as pivotal stromal components, actively orchestrating malignant behaviors. Concurrently, microRNAs (miRNAs), small non-coding RNAs, serve as potent post-transcriptional regulators and critical mediators of intercellular communication, often encapsulated within exosomes. This review provides a comprehensive analysis of the reciprocal miRNA-mediated modulation between HER2-positive breast cancer cells and CAFs. It elucidates how tumor cell-derived miRNAs reprogram normal fibroblasts into pro-tumorigenic CAFs, and how CAF-derived miRNAs, in turn, influence HER2-positive cancer cell proliferation, invasion, metastasis, and crucially, resistance to HER2-targeted therapies. Understanding this dynamic axis reveals a self-sustaining feedback loop that drives disease advancement and therapeutic evasion. This synthesis underscores the immense potential of targeting these complex miRNA-CAF interactions as a novel strategy for diagnostic, prognostic, and therapeutic interventions, aiming to overcome the persistent challenge of resistance in HER2-positive breast cancer.
    Keywords:  Cancer-associated fibroblasts; HER2-positive breast cancer; MicroRNAs; Therapeutic resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12672-026-04469-4
  18. Liver Res. 2025 Dec;9(4): 273-285
    Targeting lactic acidosis in the tumor microenvironment: Enhancing TACE efficacy in hepatocellular carcinoma.
    Shuyi Hao, Hong Yao, Haojie Yu, Lijun Wang, Tingdong Yu, Hongping Xia, Yong Zha.
      Lactic acidosis is a hallmark of the tumor microenvironment (TME) and a critical impediment to the efficacy of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). Incomplete embolization preserves viable tumor cells that amplify hypoxia-driven glycolysis, generating a lactic acid-rich milieu that drives treatment resistance, skews immune populations toward immunosuppressive phenotypes, and impairs cytotoxic T lymphocyte function. In this review, we elucidate the pathways through which lactic acidosis compromises TACE efficacy and propose novel strategies for its mitigation. We examine emerging approaches, including systemic or intra-arterial alkalization, targeted inhibition of lactate production and export, and calcium carbonate nanoparticles, and evaluate their respective merits and limitations. Finally, we propose a combination regimen of calcium carbonate nanoparticles, lactate-targeting agents, and TACE to achieve precise drug delivery, synergistic lactic acid depletion, and enhanced antitumor immunity. These integrated strategies have the potential to convert immunologically "cold" HCC lesions into "hot" ones, thereby improving TACE outcomes and disease control.
    Keywords:  Alkalization therapies; Hepatocellular carcinoma (HCC); Lactate acid inhibition; Lactic acidosis; Nanoparticles; Transarterial chemoembolization (TACE); Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.livres.2025.11.004
  19. Front Immunol. 2025 ;16 1697675
    Immune cell metabolic reprogramming in hepatocellular carcinoma: mechanisms, tumor microenvironment, and future immunotherapeutic directions.
    Lichen Zhou, Wenjie Zhang, Zhuoran Liu, Yaming Xie, Kangyi Jiang.
      Hepatocellular carcinoma (HCC), the most common primary liver cancer, continues to rank among the leading causes of cancer-related death despite improvements in early detection and systemic therapies. Therapeutic advances, including immune checkpoint blockade, cancer vaccines, and adoptive cell therapies, have broadened treatment possibilities. However, their efficacy and durability are often limited by immune evasion within a metabolically challenging tumor microenvironment (TME). This review consolidates current knowledge on how metabolic reprogramming in immune cells influences HCC progression, therapy resistance, and clinical outcomes. We discuss the roles of glycolysis, oxidative phosphorylation, fatty acid oxidation, and amino acid metabolism kynurenine pathways-in regulating the differentiation and function of T cells, regulatory T cells, macrophages, dendritic cells, natural killer cells, and B cells. Environmental factors such as hypoxia, lactate accumulation, adenosine signaling, and lipid remodeling act as key TME cues that suppress antigen presentation, impair cytotoxic responses, and promote immunosuppressive myeloid phenotypes. Building on these mechanisms, current strategies focus on targeting metabolic checkpoints in immune cells, reshaping the TME, and integrating metabolic modulation with checkpoint inhibitors to enhance therapeutic efficacy. In addition, candidate biomarkers (including circulating metabolites, multi-omics profiles, and liquid-biopsy indicators of immune metabolism) offer opportunities for patient stratification and dynamic monitoring. Together, these insights provide a conceptual framework in which precise modulation of immune metabolism can potentiate existing immunotherapies and guide rational combination strategies, warranting further clinical investigation to achieve sustained benefit in HCC.
    Keywords:  hepatocellular carcinoma; immune cell metabolism; immunotherapy; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1697675
  20. Biomed Pharmacother. 2026 Jan 26. pii: S0753-3322(26)00079-X. [Epub ahead of print]195 119047
    The tumor ecosystem: Rewiring an open, systemically integrated network for therapeutic gain.
    Paola Chiodelli, Andrea Papait, Lorenzo Agoni, Federico Quaglia, Antonietta Rosa Silini, Ornella Parolini.
      Despite the tumor microenvironment (TME) being a major therapeutic focus, the clinical translation of TME-targeted agents has been largely unsuccessful, a paradox that challenges paradigms rooted in a reductionist view of the TME as a self-contained entity. We propose a framework redefining the TME as an open, multi-scalar ecosystem dynamically shaped by systemic host factors. Locally, cancer-associated fibroblasts (CAFs), myeloid cells and the vasculature act not as isolated cell types but as integrated components of functional niches that orchestrate fibrosis, immunosuppression and angiogenesis. Systemically, the gut microbiome and chronic inflammation of ageing ('inflammaging') pre-condition the host terrain and modulate therapeutic responses across this network. Viewed through this systemic lens, resistance emerges not as molecular bypass but as ecological adaptation of a complex, open system. We argue that next-generation therapies will depend on spatial omics to map pathological niches and on rational, multimodal strategies that explicitly target the TME as a systemically integrated network.
    Keywords:  Cancer associated fibroblasts; Inflammaging; Microbiome; Therapeutic reprogramming; Tumor ecosystem; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2026.119047
  21. Exp Hematol Oncol. 2026 Jan 29. 15(1): 14
    Stem cell engineering for the generation of allogeneic CAR-directed natural killer T cells targeting endometrial carcinoma.
    Yan-Ruide Li, Gabriella A DiBernardo, Yuning Chen, Xinyuan Shen, Ryan Hon, Lauryn E Ruegg, Jie Huang, Adam Neal, Neda A Moatamed, Sanaz Memarzadeh, Lili Yang.
       BACKGROUND: Aggressive subtypes of uterine endometrial carcinoma (UEC) often result in mortality due to recurrence of disease with chemoresistant tumor cells surrounded by an immune suppressive microenvironment. Current CAR-T cell therapies have shown limited efficacy in solid tumors, largely constrained by poor tumor infiltration, immune suppression, and the logistical limitations of autologous cell production, which hinder broad patient access.
    METHODS: In this study, we conducted comprehensive immunophenotyping of primary UEC patient samples and identified a therapeutic opportunity for CAR-engineered invariant natural killer T (CAR-NKT) cells capable of targeting both tumor cells and the immunosuppressive TME. Using a hematopoietic stem and progenitor cell (HSPC) engineering platform coupled with ex vivo differentiation culture, we generated allogeneic mesothelin-targeting CAR-NKT cells (AlloMCAR-NKT) with high purity and yield.
    RESULTS: AlloMCAR-NKT cells exhibited potent cytotoxic activity against UEC tumor cells and CD1d⁺ tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Importantly, compared to conventional CAR-T cells, AlloMCAR-NKT cells demonstrated an improved safety profile, showing no evidence of graft-versus-host disease (GvHD) and minimal cytokine release syndrome (CRS)-related toxicity.
    CONCLUSION: These findings highlight the potential of AlloMCAR-NKT cells as a safe and effective off-the-shelf cellular immunotherapy for the treatment of UEC and potentially other solid tumors characterized by an immunosuppressive microenvironment.
    Keywords:  Allogeneic CAR-NKT cells; Allogeneic cell therapy; Antigen escape.; Chimeric antigen receptor (CAR); Mesothelin (MSLN); Multiple tumor targeting mechanism; Natural killer T (NKT) cell; Off-the-shelf; Potent antitumor activity; Stem cell engineering; Tumor microenvironment (TME); Tumor-associated macrophage (TAM); Uterine endometrial carcinoma (UEC)
    DOI:  https://doi.org/10.1186/s40164-026-00746-8
  22. Adv Healthc Mater. 2026 Jan 28. e04890
    Metadherin with Stromal-Immune Cues Drives CD36-Dependent Lipid Reprogramming and Metastasis in Triple-Negative Breast Cancer: Insights from a Hetero-Spheroid Model.
    Soumyadeep Poddar, Shashikanta Sahoo, Yogesh Chandra, Sandeep Shrivastava, Srigiridhar Kotamraju, Biswajit Saha.
      Triple-negative breast cancer (TNBC) exhibits altered lipid metabolism, driven by the tumor microenvironment's cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). CD36, a fatty acid translocase, is crucial in this metabolic adaptation of cancer cells. Despite its importance, what controls CD36-mediated lipid flow is still unclear. This study identifies metadherin (MTDH), an oncogene, as a critical regulator of CD36-dependent lipid exchange and TNBC progression. Using engineered spheroid models that mimic tumor microenvironment with MTDH-Wt and MTDHΔ7 overexpressing TNBC cells co-cultured with CAFs and TAMs, we observed increased lipid uptake, enhanced EMT, and aggressive metastatic features driven by MTDH-CD36 signaling. Further analyses, including advanced microscopy and transcriptomics, revealed that MTDHΔ7 overexpression in TNBC cells in the presence of stromal-immune cells, amplifies lipid metabolic pathways, promotes stemness, and pro-metastatic signaling. Intriguingly, increased formation of tunnelling nanotube-like structures, indicative of metabolic rewiring, was observed in Lv.MTDHΔ7-MDA-MB-231CAF-TAM heterotypic spheroids. These changes were reversed by sulfosuccinimidyl oleate (SSO; CD-36 inhibitor) treatment. Moreover, SCID mice bearing Lv.MTDH-Wt/Δ7-MDA-MB-231cellsCAF-TAM heterotypic spheroids led to accelerated breast tumor growth and lipid-driven metastasis. Importantly, SSO administration significantly reduced lipid accumulation and tumor aggressiveness, confirming CD36 as a functional mediator of MTDH-driven lipid reprogramming. Our findings establish MTDH as a master regulator of lipid reprogramming through CD36, a process further amplified by CAF-TAM interactions, which creates a lipid-rich tumor microenvironment fuelling TNBC aggressiveness. This study reveals crucial mechanistic insights into how stromal-immune cells induce lipid symbiosis and highlights the MTDH-CD36 axis as a promising therapeutic target for future combination therapies in aggressive, metabolically reprogrammed TNBC.
    Keywords:  CD36; MTDH; TNBC; heterotypic spheroids; lipid reprogramming
    DOI:  https://doi.org/10.1002/adhm.202504890
  23. Cell Commun Signal. 2026 Jan 29.
    Targeting sensory nerves in the tumor microenvironment: a new vulnerability in cancer therapy.
    Jun Jiang, Zhe Xu, Danyu Qu, Jiayang Qin, Weihong Wen, Weijun Qin, Donghui Han.
      Tumor innervation, the infiltration of nerves into the tumor microenvironment (TME), is increasingly recognized as a novel hallmark driving cancer progression and is associated with poor patient prognosis across various solid malignancies. This process is orchestrated by a complex, bidirectional crosstalk. Cancer and stromal cells release neurotrophic factors that induce axonogenesis or neurogenesis. In turn, the infiltrating nerves, particularly sensory nerves, secrete neurotransmitters, neuropeptides or form pseudo-synapse with tumor cells to facilitate cancer hallmarks, including sustained proliferation, invasion, metastasis, modulation of the anti-tumor immune response, and cancer plasticity. However, the specific contributions and underlying mechanisms of sensory nerve innervation in orchestrating malignancy remain incompletely elucidated. This review aims to synthesize the current understanding of the multifaceted roles of sensory neurons within the TME, detailing their intricate interactions with cancer and stromal cells, and highlighting the emerging therapeutic strategies that target the sensory nerve-tumor axis.
    Keywords:  Peripheral nervous system; Sensory nerve; Tumor innervation; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12964-025-02637-7
  24. Front Immunol. 2026 ;17 1774012
    Editorial: Immuno-metabolic interactions and cancer progression in the tumor microenvironment.
    Vincenzo Flati, Jacopo Di Gregorio, Nahum Puebla-Osorio, Khosrow Kashfi.
      
    Keywords:  cancer; cancer immunity & immunotherapy; cancer metabolism; immuno-metabolic crosstalk; tumor microenvironment - TME
    DOI:  https://doi.org/10.3389/fimmu.2026.1774012
  25. Curr Issues Mol Biol. 2026 Jan 20. pii: 106. [Epub ahead of print]48(1):
    Regulatory B Cells in Tumor Microenvironment.
    Zhuoyan Cai, Lin Xie.
      Regulatory B cells (Bregs) are integral to the tumor microenvironment (TME) and influence immune responses through the secretion of immunosuppressive cytokines such as IL-10, IL-35, and TGF-β. This review highlights recent findings on the phenotype and mechanisms of Bregs, emphasizing their dual role in regulating immune responses within the TME. Importantly, we further explored the latest advances in Breg regulatory mechanisms from the novel perspectives of epigenetics and metabolic remodeling, including the effects of DNA methylation, histone acetylation, glycolysis, and oxidative phosphorylation on Bregs. We also investigate the therapeutic targeting of Bregs, with a focus on STAT3 inhibitors such as lipoxin A4, cucurbitacins, and resveratrol, which show promising potential in mitigating the suppressive function of Bregs. Furthermore, this review provides a detailed analysis of the impact of Bregs on tumorigenesis and metastasis, emphasizing the importance of inhibiting specific immune pathways to prevent tumor escape. Finally, this review offers a prospective outlook on immunotherapy strategies based on Bregs, foreseeing a more nuanced understanding of their TME function and the evolution of targeted treatments with enhanced therapeutic efficacy.
    Keywords:  epigenetics; metabolic remodeling; regulatory B cells; tumor immunity; tumor immunotherapy
    DOI:  https://doi.org/10.3390/cimb48010106
  26. Crit Rev Oncol Hematol. 2026 Jan 23. pii: S1040-8428(26)00037-5. [Epub ahead of print]219 105150
    KRAS mutations reshape the immunosuppressive tumor microenvironment in triple-negative breast cancer: A novel perspective.
    Yuanhao Lv, Ziyin Zhao, Wenyu Di, Lei Liu, Yiyang Chen, Wei Su, Yinghua Ji, Jiateng Zhong.
      Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by poor prognosis and limited therapeutic options due to the lack of well-defined molecular targets. While conventional studies have primarily focused on tumor cell-intrinsic oncogenic mechanisms, this article presents a novel perspective emphasizing the pivotal role of KRAS mutations in remodeling the tumor microenvironment (TME) of TNBC. Although KRAS mutations are relatively uncommon in TNBC (approximately 2-5 %), their presence is associated with increased tumor aggressiveness, the establishment of an immunosuppressive microenvironment, and poor clinical outcomes. This review systematically explores how KRAS mutations, potentially through the modulation of NADPH oxidase 2 (NOX2) activity, may alter oxidative stress dynamics within the TME. We propose that this axis impairs immune cell function, facilitating immune evasion and therapeutic resistance. This perspective not only deepens our understanding of the mechanisms underlying the malignant progression of TNBC but also provides a theoretical basis for developing novel therapeutic strategies to overcome current treatment challenges.
    Keywords:  KRAS mutation; NOX2; ROS; TNBC; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105150
  27. Int J Surg. 2026 Jan 28.
    Myeloid-derived suppressor cells promote therapy-induced resistance in prostate cancer.
    Anlin Liu, Pan Song, Zhenghuan Liu, Manuel Colucci, Ping Lai, Luchen Yang, Xin Yan, Haiyun Qiu, Qiang Dong.
      Androgen deprivation therapy (ADT) is the standard treatment for prostate cancer (PCa), but it is often followed by the development of resistance, leading to the progression of castration-resistant prostate cancer. A key factor influencing treatment response, disease progression, and prognosis is the tumor immune microenvironment. Notably, the accumulation of myeloid-derived suppressor cells (MDSCs) within the tumor creates an immunosuppressive milieu, contributing to treatment failure. Interactions between MDSCs and tumor cells in PCa have been shown to drive castration resistance and facilitate tumor progression. Targeting this immunosuppressive microenvironment holds significant promise for improving therapeutic outcomes. Strategies to target MDSCs include modulating their immunosuppressive activity, promoting their maturation, or inducing their apoptosis. While monotherapy with immunotherapy has shown limited survival benefits in PCa, combining MDSC-targeted therapies with immunotherapy may significantly enhance treatment efficacy and patient outcomes. This review aims to examine the role of MDSCs in therapy resistance and explore potential strategies for targeting them in PCa.
    Keywords:  androgen deprivation therapy; castration-resistant; myeloid-derived suppressor cells; prostate cancer
    DOI:  https://doi.org/10.1097/JS9.0000000000004227
  28. Front Immunol. 2025 ;16 1697008
    Lactylation in cancer: mechanistic insights, tumor microenvironment, and therapeutic horizons.
    Qiang Yang, Zhibo Yang, Hai Zhao.
      The discovery of lactylation, a post-translational modification derived from lactate, has fundamentally altered the perception of cancer metabolism. Once regarded as a metabolic waste product, lactate is now recognized as a central fuel source, a signaling molecule, and an epigenetic substrate capable of reprogramming gene expression and cellular function. Lactylation integrates metabolic reprogramming, tumor plasticity, and immune suppression, thereby orchestrating cancer initiation, progression, and resistance to therapy. This review provides a critical and integrative commentary on recent advances in lactylation biology, drawing from biochemical, epigenetic, and immunological perspectives. It synthesizes mechanistic insights into lactylation, highlights its role in tumorigenesis and the tumor microenvironment (TME), and evaluates therapeutic strategies that target lactate production, transport, and lactylation machinery. By dissecting consensus, controversies, and unresolved questions, we argue that lactylation represents both a hallmark of tumor adaptation and a potential Achilles' heel for intervention. We further discuss future research directions, including comprehensive lactylome mapping, structural biology of lactylated proteins, microbiome-derived lactate, and clinical translation. Ultimately, lactylation is not merely a byproduct of glycolysis but a metabolic language that tumors employ to communicate, adapt, and thrive. Decoding this language may open new frontiers in cancer therapy.
    Keywords:  cancer immunotherapy; epigenetic regulation; histone modi7ication; immunometabolism; lactylation; therapeutic targets; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1697008
  29. Front Immunol. 2025 ;16 1703277
    Fibroblast-immune crosstalk in oral squamous cell carcinoma: from tumor promotion to immune evasion.
    Xiao Liu, Dandan Wang, Xue Cheng, Yining Ma, Siya Li, Jinhai Deng, Chunyan Qiao.
      Oral squamous cell carcinoma (OSCC) is a highly invasive malignancy marked by poor prognosis and therapeutic resistance. Within its tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) and immune cells form a dynamic network that drives tumor progression. CAFs reshape the extracellular matrix, rewire tumor metabolism, and modulate immune surveillance by recruiting regulatory T cells and promoting macrophage polarization. Recent studies have highlighted CAF heterogeneity, identifying functionally distinct subtypes with differential impacts on prognosis and treatment responsiveness. CAF-derived secretomes, including cytokines, chemokines, and exosomal miRNAs, shape tumor-immune dynamics and mediate resistance to cisplatin and anti-angiogenic therapies. Crosstalk between CAFs and immune cells, particularly via the IL-6-STAT3-PD-L1 and CXCL12-CXCR4 axes, promotes immune evasion and dampens responses to checkpoint blockade. This review summarizes the phenotypic heterogeneity, metabolic functions, and secretory profiles of CAFs in OSCC, with particular emphasis on their crosstalk with immune components, highlighting the potential of CAFs-targets to enhance immunotherapy responsiveness.
    Keywords:  cancer-associated fibroblasts; extracellular matrix; immune crosstalk; immune suppression; metabolic reprogramming; oral squamous cell carcinoma; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1703277
  30. Expert Rev Clin Immunol. 2026 Jan 27.
    CAR-T cell immunotherapy of malignant melanoma.
    Olha Kharasakhal, John Maher.
       INTRODUCTION: Management of inoperable and advanced malignant melanoma has been transformed in recent years by the advent of a number of approaches, including immune checkpoint blockade, small molecule inhibitors and adoptive immunotherapy with ex vivo expanded tumor-infiltrating lymphocytes.
    AREAS COVERED: In this review, we describe efforts made to develop an alternative immunotherapeutic approach for this disease using chimeric antigen receptor (CAR) engineered T-cells. Literature was reviewed in the PubMed database and clinicaltrials.gov website (1998-2025).
    EXPERT OPINION: CAR T-cell immunotherapy has proven transformative in the treatment of selected hematological malignancies. However, solid tumors such as melanoma remain much more challenging to treat using this emerging modality. Here we consider issues surrounding target selection, encompassing both tumor cells and accompanying stroma, in addition to armoring approaches that may potentiate delivery to or efficacy within the tumor microenvironment. We also consider a number of advanced CAR-based architectures to enable multi-antigen or universal antigen targeting and combination-based approaches.
    Keywords:  CAR armoring; CAR combination therapies; CAR macrophages; CAR manufacture; Chimeric antigen receptor (CAR); NK cells; NKT-cells; cancer immunotherapy; dual targeting; gd T-cells; malignant melanoma; target selection; tumor microenvironment (TME); universal CAR
    DOI:  https://doi.org/10.1080/1744666X.2026.2621811
  31. Oncol Res. 2026 ;34(2): 10
    Cancer-Associated Fibroblasts in Prostate Cancer: Unraveling Mechanisms and Therapeutic Implications.
    Yang Wu, Dong Xu, Run Shi, Mingwei Zhan, Shaohui Xu, Xin Wang, Jianpeng Zhang, Zhaokai Zhou, Weizhuo Wang, Yongjie Wang, Minglun Li, Zihao Xu, Kaifeng Su.
      Prostate cancer (PCa) remains a major cause of cancer-related mortality in men, largely due to therapy resistance and metastatic progression. Increasing evidence highlights the tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), as a critical determinant of disease behavior. CAFs constitute a heterogeneous population originating from fibroblasts, mesenchymal stem cells, endothelial cells, epithelial cells undergoing epithelial-mesenchymal transition (EMT), and adipose tissue. Through dynamic crosstalk with tumor, immune, endothelial, and adipocyte compartments, CAFs orchestrate oncogenic processes including tumor proliferation, invasion, immune evasion, extracellular matrix remodeling, angiogenesis, and metabolic reprogramming. This review comprehensively summarizes the cellular origins, phenotypic and functional heterogeneity, and spatial distribution of CAFs within the prostate TME. We further elucidate the molecular mechanisms by which CAFs regulate PCa progression and therapeutic resistance, and critically evaluate emerging strategies to therapeutically target CAF-mediated signaling, metabolic, and immune pathways. By integrating recent advances from single-cell and spatial transcriptomics (ST), our objective is to provide a holistic framework for understanding CAF biology and to highlight potential avenues for stromal reprogramming as an adjunct to current PCa therapies.
    Keywords:  Prostate cancer; cancer-associated fibroblasts; therapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.32604/or.2025.073265
  32. Mol Biomed. 2026 Jan 30. 7(1): 9
    TGF-β in tumor development and progression: mechanisms and therapeutics.
    Jialing Liu, Yiwei Wang, Chao Tang, Lulu Zhang, Sidong Xiong, Jun Wang, Chunsheng Dong.
      Transforming growth factor beta (TGF-β) is a pleiotropic cytokine and participates in multiple cellular processes, such as cell development, proliferation, epithelial mesenchymal transition (EMT), and immune responses through SMAD-dependent or SMAD-independent signaling pathways. Notably, TGF-β signaling plays a dual role in tumors, acting as a potent tumor suppressor during early tumorigenesis by inducing apoptosis or cell-cycle arrest while promoting tumor transformation, progression and metastasis in advanced stage through multidimensional mechanisms. Moreover, it is abundant and functions as a master immune checkpoint in the tumor microenvironment (TME), fostering the development of numerous targeted therapies to rectify its aberrant activity in tumors in the past decades. Thus, a comprehensive overview of the pathologic roles, molecular mechanisms and therapeutic potentials of TGF-β signaling in tumors will benefit both the basic and clinical cancer research. Here, we review the complex biology and context-dependent functions of the TGF-β superfamily in regard to tumor, highlighting how it regulates the latter's development, growth, and dissemination by mainly targeting tumor cells, tumor-associated fibroblasts and various immune cells. We also summarize recent advances in the preclinical and clinical development of different types of TGF‑β‑targeting agents, and discuss their therapeutic potentials and challenges as well as approaches to improve the safety and efficacy of TGF-β pathway-targeted therapy in cancers. Through the summary of known knowledge and the latest updates, this review may provide a general picture on the biological functions of TGF-β in tumors, and facilitate the clinical implications of TGF-β-targeted therapy in tumor patients.
    Keywords:  Anti-tumor immunity; Metastasis; TGF-β signaling; TGF-β-targeting therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s43556-026-00403-w
  33. J Biomech. 2026 Jan 20. pii: S0021-9290(26)00024-2. [Epub ahead of print]197 113170
    Decoding the mechanical language of the tumor microenvironment: From physical forces to malignant behaviors.
    Luyao Zhao, Yifan Han, Jing Du, Xinbin Zhao.
      Malignant metastasis, the leading cause of cancer mortality, is initiated by tumor invasion, a process intrinsically linked to dynamic biomechanical alterations within the tumor microenvironment (TME). While recent reviews have established the role of extracellular matrix (ECM) stiffness, this review offers a distinct synthesis by focusing on the synergistic interplay between two critical, yet underappreciated, mechanical forces: solid stress and fluid pressure. We propose that these forces form an integrated mechanical barrier that actively promotes malignancy. As tumors grow, ECM deposition and spatial confinement generate substantial solid stress, while vascular dysfunction elevates fluid stress. This review uniquely details how this solid-fluid stress nexus drives malignant progression, immune suppression, and therapeutic resistance through coordinated mechanobiological signaling. We comprehensively synthesize how these altered forces regulate tumor cell behavior by focusing on mechanotransduction-the conversion of mechanical cues into biochemical signals. Finally, we outline a framework for novel therapeutic strategies that target this "physical barrier", with the goal of improving drug delivery, overcoming resistance, and advancing cancer treatment.
    Keywords:  Biomechanics; Fluid stress; Mechanotransduction; Metastasis; Solid stress; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jbiomech.2026.113170
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