bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–10–19
23 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Crosstalk between tumor-associated macrophages and the B7/CD28 family in immune checkpoint inhibitor-induced immunotherapy.
  2. Reprogramming the immune microenvironment in lung cancer.
  3. Metabolites in the extracellular tumor microenvironment and the shaping of macrophage function.
  4. Glutamine: a new strategy for targeted metabolic therapy in the tumor microenvironment.
  5. Tumor-associated macrophages: untapped molecular targets to improve T cell-based immunotherapy.
  6. Bimetallic Nanozyme Amplifier for Synergistic Ferroptosis-Cuproptosis and Metabolic Reprogramming to Reshape Immunosuppressive Tumor Microenvironment.
  7. The role of lipid metabolic interactions in reshaping the tumor microenvironment.
  8. Microenvironmental regulation of solid tumour resistance to CAR T cell therapy.
  9. Macrophages: Traffic centers in the tumor immune microenvironment.
  10. The role of fatty acid oxidation in the tumor microenvironment: Implications for cancer progression and therapeutic strategies.
  11. MDSCs in breast cancer: metastasis, lipid metabolism, and therapeutics.
  12. Envirotune-CAR-T: a hypoxia-responsive and glutamine-enhanced CAR-T cell therapy for overcoming tumor microenvironment-mediated suppression.
  13. The Role of Tumor-Intrinsic HuR in Modeling the Pancreatic Tumor Microenvironment: Molecular Mechanisms and Therapeutic Opportunities.
  14. Exosomal miRNAs: Key Regulators of the Tumor Microenvironment and Cancer Stem Cells.
  15. The metabolic regulation of tumor-associated macrophage reprogramming.
  16. Gene Signature-Based Drug Screening Reveals Ponatinib Enhances Immunotherapy Efficacy in Triple-Negative Breast Cancer by Reversing MDSC-Mediated Immunosuppressive Tumor Microenvironment.
  17. Role of macrophage PKM2 in inflammation and tumor progression and its targeted therapy.
  18. Protein engineering to overcome limitations of key cytokines in cancer immunotherapy: current approaches and future perspectives.
  19. Ferroptosis as a precise target for tumor-associated neutrophils: From molecular insights to targeted therapies.
  20. Enhanced Collagen Prolyl 4-Hydroxylase Activity and Expression Promote Cancer Progression via Both Canonical and Non-Canonical Mechanisms.
  21. Glycolytic Reprogramming in Oral Squamous Cell Carcinoma: Molecular Regulators and Natural Product-Based Therapies.
  22. Tumor microenvironment and macroenvironment: A new perspective on holistic oncology.
  23. Targeting triple-negative breast cancer using cord-blood CD34⁺ HSPC-derived mesothelin-specific CAR-NKT cells with potent antitumor activity.
  1. Mol Cell Biochem. 2025 Oct 13.
    Crosstalk between tumor-associated macrophages and the B7/CD28 family in immune checkpoint inhibitor-induced immunotherapy.
    Rui Bai, Wenjie Sun.
      The tumor microenvironment (TME) is a complex ecosystem containing various cells and secreted molecules that play critical roles in the progression of tumorigenesis. In recent years, antitumor strategies aimed at reshaping the TME have attracted much attention. Tumor-associated macrophages (TAMs) are the most abundant immune cells infiltrating the TME, contributing more than 50% of the tumor mass. In a variety of cancers, TAMs participate in the processes of tumor formation, migration, and invasion and are significantly related to a poor prognosis. Furthermore, TAMs play crucial roles in the regulation of the TME, chemoresistance, and immunotherapy resistance, and are potential targets in tumor therapy. TAMs are supposed to be carriers of ligands of immune checkpoint inhibitors (ICIs). Therefore, it is expected that TAMs can regulate T cell immune function through providing costimulatory/coinhibitory signals and may significantly influence the immune response related to ICIs. B7/CD28 family members are the best studied immune checkpoint receptors and ligands. Several studies have demonstrated that these B7/CD28 family members are highly expressed on TAMs, eliminating the inhibitory signal of T cell activation. However, the role of TAMs and B7/CD28 family members in ICI-induced immunotherapy is complicated and need to be illustrated. This study aims to review the crosstalk between TAMs and the B7/CD28 family, highlight the role of TAM-mediated tumor immune escape in ICI immunotherapy, explore the application prospects of TAMs in reversing ICI resistance.
    Keywords:  B7/CD28; Immune checkpoint inhibitors (ICIs); Immune resistance; Macrophage reprogramming; Tumor microenvironment (TME); Tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.1007/s11010-025-05405-w
  2. Front Immunol. 2025 ;16 1684889
    Reprogramming the immune microenvironment in lung cancer.
    Kai Chen, Linqi Luo, Yong Li, Ge Yang.
      Lung cancer remains the leading cause of cancer-related mortality worldwide, with its progression shaped not only by tumor-intrinsic factors but also by a complex and immunosuppressive tumor microenvironment (TME). Within this niche, diverse immune populations-including CD8+ cytotoxic T cells, CD4+ helper T cell subsets (Th1, Th17, Tregs), B cells, natural killer (NK) cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs)-collectively regulate immune surveillance and tumor escape. While effector lymphocytes mediate antitumor responses, their function is often attenuated by TAM- and MDSC-driven immunosuppression via cytokines (IL-10, TGF-β), metabolic disruption, and immune checkpoint expression. High densities of M2-polarized TAMs and MDSCs correlate with poor prognosis and resistance to therapy. Immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 have improved outcomes in lung cancer, yet therapeutic efficacy remains limited by the immunosuppressive TME. This review outlines the functional roles of key immune cell subsets in lung cancer and highlights emerging strategies to reprogram the TME and enhance immunotherapeutic responsiveness.
    Keywords:  MDSC; TAM; immune evasion; immunotherapy; lung cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1684889
  3. Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00776-2. [Epub ahead of print]85(20): 3779-3792
    Metabolites in the extracellular tumor microenvironment and the shaping of macrophage function.
    Sara Lamorte, Matthew Bianca, Zhe Qi Liu, Tracy L McGaha.
      It has been a century since it was discovered that cancer cells have a distorted metabolism compared to healthy cells and tissues. It is now universally accepted that the abnormal metabolic state of cancers is essential for proliferation and survival in the harsh environment of most solid tumors. However, the impact of the altered metabolite pools generated from this rewiring is complex and has been challenging to functionally disentangle. Macrophages are innate immune cells and a major cellular constituent of the tumor microenvironment (TME). Macrophages are functionally plastic and highly sensitive to changes in metabolite exposure, with the potential to change the TME in a profound, disease-altering fashion. However, it was not until the recent advent of sensitive, high-dimensional analysis that the impact of metabolites on tumor macrophage diversity and function was fully appreciated. In this review, we discuss recent developments in our knowledge of how altered metabolites, resulting from metabolic reprogramming in the TME, influence macrophage phenotype and the implications for tumor development and progression. Furthermore, we examine emerging therapeutic strategies aimed at targeting tumor-metabolite crosstalk to improve disease outcomes.
    Keywords:  immunity; macrophage; metabolism; metabolites; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.016
  4. Cell Death Discov. 2025 Oct 13. 11(1): 459
    Glutamine: a new strategy for targeted metabolic therapy in the tumor microenvironment.
    Haixu Lv, Xiao Han, Yuanshuang Yang, Jianfeng Shen, Yixuan Yin, Yu Liu.
      In the tumor microenvironment, glutamine has a profound impact not only on the growth, metabolism, metastasis, and invasion of tumor cells but also on the survival and function of immune cells and the behavior of nonimmune cells. Given the limited amount of glutamine in the tumor microenvironment, there is a competitive relationship between tumor and nontumor cells. Owing to the metabolic reprogramming of tumor cells, many nutrients, including glutamine, are necessary for tumor cells to maintain their rapid growth and high metabolic demand. Therefore, tumor cells are in a superior position to compete for glutamine. These findings provide solid theoretical support for targeting glutamine metabolism for anticancer therapy. This review summarizes the importance and necessity of glutamine for tumor cells and nontumor cells in the tumor microenvironment. According to the mechanism of action of glutamine in tumor cells and the regulatory mechanism of related signaling pathways, the currently developed anticancer drugs that target glutamine metabolism are categorized on a scientific basis, and the importance of basic medicine applied in clinical medicine is emphasized. This review not only provides anticancer information for clinicians but also brings hope to cancer patients.
    DOI:  https://doi.org/10.1038/s41420-025-02767-4
  5. Mol Cancer. 2025 Oct 16. 24(1): 261
    Tumor-associated macrophages: untapped molecular targets to improve T cell-based immunotherapy.
    Rui M L Coelho, Reno Debets, Dora Hammerl.
      T cell responses are generally curtailed by suppressive mechanisms within the tumor microenvironment (TME) that prevent T cell infiltration and function. Consequently, T cell-based therapies for solid tumors have yielded limited and often non-durable clinical responses. Tumors develop a hostile TME, where tumor-associated macrophages (TAMs) that initially support T cells are converted into immune suppressive TAMs that facilitate tumor evasion from T cell control. In fact, immune suppressive TAMs represent a dominant fraction of immune cells within the TME and their presence is associated with poor prognosis and resistance to immunotherapy. Often in close contact with effector T cells, TAMs directly suppress CD8+ T cells through mechanisms involving metabolic mediators, co-signaling receptors, their ligands and/or cytokines. Here, we revisit molecular interactions behind TAM-mediated suppression of T cell responses and address the potential targeting of such molecules and pathways to re-boost anti-tumor T cell immunity. This perspective, focusing on molecular interactions between TAM and T cells, may aid the improvement of T cell-based therapies for solid tumors.
    Keywords:  AhR; B7-H4; Gal-3; Siglec-15; Siglec-9; T cell suppression; Tumor-associated macrophages; VISTA
    DOI:  https://doi.org/10.1186/s12943-025-02481-w
  6. Adv Sci (Weinh). 2025 Oct 15. e12764
    Bimetallic Nanozyme Amplifier for Synergistic Ferroptosis-Cuproptosis and Metabolic Reprogramming to Reshape Immunosuppressive Tumor Microenvironment.
    Jianzhang Luo, Kunzhao Huang, Xiaoyuan Yi, Pei Lu, Huaying Xie, Wen Li, Qingyu Zeng, Feifei He, Duo Wang, Liyan Wang.
      Although ferroptosis and cuproptosis have shown potential in tumor therapy, their anti-tumor efficacy remains considerably limited due to aberrant metabolism within tumor cells and the immunosuppressive tumor microenvironment (TME). Herein, metal-organic framework nanoparticles (PEG@AuCZ@CC) are engineered by incorporating Au nanoparticles and α-Cyano-4-hydroxycinnamic acid (CHCA), to maximize hydrogen peroxide production and induce metabolic shift from aerobic glycolysis to oxidative phosphorylation in tumor cells. Interestingly, metabolic reprogramming of tumor cells not only enhances both ferroptotic and cuproptotic signaling cascades, amplifies immunogenic cell death (ICD) effects, but also reduces intratumoral glucose consumption and extracellular lactate accumulation, thereby creating a glucose-enriched but lactate-depleted TME. Consequently, the platform significantly promotes dendritic cells maturation, enables epigenetic reprogramming of tumor-associated macrophages (TAMs), and restores CD4⁺/CD8⁺ T-cells functionality. This multimodal strategy reshapes the tumor microenvironment (TME) by integrating cell death modulation and cell metabolism regulation, effectively overcoming immune tolerance, presenting a promising paradigm for hepatocellular carcinoma (HCC) therapy.
    Keywords:  TME reprogramming; cuproptosis; ferroptosis; metabolic reprogramming; nanozyme
    DOI:  https://doi.org/10.1002/advs.202512764
  7. Acta Biochim Biophys Sin (Shanghai). 2025 Oct 15.
    The role of lipid metabolic interactions in reshaping the tumor microenvironment.
    Ruyin Yang, Shiyu Liu, Yingqi Bi, Ruize Jin, Zixin Ye, Xinfei Cai, Ann M Bode, Wenbin Liu, Xiangjian Luo.
      The tumor microenvironment (TME), which encompasses the extracellular matrix, cancer-associated fibroblasts, endothelial cells, pericytes, and immune cells, is intimately connected to tumor development and metastasis. TME is widely heterogeneous, and metabolic interactions among the different components contribute to reshaping TME. Lipid metabolism, referring to lipid uptake, synthesis, transport, and lipolysis, is essential for maintaining cellular homeostasis. The availability of nutrients in the TME constantly changes during tumor progression, and tumor cells must reprogram lipid metabolism to maintain their rapid proliferation, survival, invasion, and metastatic potential. The interactions of lipid metabolism among tumor cells and other cell subtypes reshape the microenvironment into a niche suitable for tumor development. In this review, we present the featured lipid metabolic interactions within the TME of different cancer types and discuss how targeting abnormal lipid metabolic pathways could be a promising strategy for cancer therapeutics.
    Keywords:  lipid metabolic interaction; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3724/abbs.2025166
  8. Nat Rev Immunol. 2025 Oct 14.
    Microenvironmental regulation of solid tumour resistance to CAR T cell therapy.
    Zachary L Lamplugh, Nils Wellhausen, Carl H June, Yi Fan.
      Chimeric antigen receptor (CAR) T cell therapy holds significant promise for the treatment of cancer; however, its efficacy in solid tumours is substantially hindered by the immunosuppressive tumour microenvironment (TME). Solid tumours can resist immunotherapy by impairing T cell trafficking, function and persistence. One of the initial obstacles that CAR T cells encounter is the abnormal tumour vasculature, which restricts efficient T cell infiltration, further compounded by a dense extracellular matrix. CAR T cells that do infiltrate the tumours are outnumbered by immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages. Additionally, tumour cells can contribute to CAR T cell resistance by upregulating immune checkpoint molecules, such as PDL1 and CTLA4, and engage in metabolic competition. In this Review, we discuss how cellular and non-cellular components of the TME impair CAR T cell therapy and consider potential strategies to improve CAR T cell therapies for solid tumours, either by reprogramming the TME or by engineering CAR T cells to resist the immunosuppressive effects of the TME.
    DOI:  https://doi.org/10.1038/s41577-025-01229-3
  9. Cell Immunol. 2025 Oct 09. pii: S0008-8749(25)00123-6. [Epub ahead of print]418 105037
    Macrophages: Traffic centers in the tumor immune microenvironment.
    Fan Zou, Yishan Zhang, Mingdong Wang, Yongjun Quan, Hao Ping.
      The tumor microenvironment (TME) has emerged as a prominent focus of cancer research in recent years, with various drugs in this field, including programmed cell death receptor 1 (PD-1) antibodies and cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, now included in first-line therapeutic guidelines for cancer. Although macrophages are not as effective as T-lymphocytes in directly killing tumors, they serve as critical mediators in the TME due to their indirect roles in promoting blood vessel formation, facilitating antigen presentation and influencing tumor cell metabolism to affect their infiltration. Macrophages are governed by complex regulatory networks, both independently and as a part of the TME. Extensive research has led to the development of a comprehensive and detailed understanding of these networks and the molecular mechanisms driving macrophage activity. The interactions between macrophages and the TME significantly impact tumor initiation and progression, making macrophages a promising target for cancer therapy. In this review, we discuss recent findings on the factors underlying macrophage polarization in the TME, the critical role of macrophages within the TME, key transcriptional regulators of macrophages, and emerging strategies for targeting macrophages in cancer therapy.
    Keywords:  Cytokine; Immune infiltration; Immunotherapy; Macrophage; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cellimm.2025.105037
  10. Biochim Biophys Acta Rev Cancer. 2025 Oct 10. pii: S0304-419X(25)00216-1. [Epub ahead of print]1880(6): 189474
    The role of fatty acid oxidation in the tumor microenvironment: Implications for cancer progression and therapeutic strategies.
    Nasot Rashed, Wenbin Liu, Xiangjian Luo.
      Fatty acid oxidation (FAO), or β-oxidation, is a catabolic process that breaks down fatty acids into acetyl-CoA. FAO plays a pivotal role in the metabolic reprogramming of cancer cells and the tumor microenvironment (TME), serving as a crucial energy source that sustains cellular functions under conditions of nutrient deprivation and metabolic stress. This process significantly influences cancer cell survival, proliferation, metastasis, and therapeutic resistance. In this review, we discuss the biological functions of FAO in cancer cells, immune cells, and stromal cells, with a particular focus on its regulatory role in tumor progression and therapy resistance. Furthermore, we explore FAO inhibitors and emerging therapeutic strategies targeting FAO as a potential approach to disrupting tumor metabolism and enhancing cancer treatment efficacy.
    Keywords:  Cancer progression; Fatty acid oxidation; Immune cells; Stromal cells; Therapeutic resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189474
  11. Mol Cancer Res. 2025 Oct 14.
    MDSCs in breast cancer: metastasis, lipid metabolism, and therapeutics.
    Ukjin Kim, Rumela Chakrabarti.
      Myeloid-derived suppressor cells (MDSCs) are one of the major contributors to the immunosuppressive microenvironment of breast cancer (BCa). MDSCs have unique mechanisms for each BCa metastasis site, and lipid metabolism acts as an energy source necessary to perform the role of MDSCs. In addition, MDSCs show different characteristics depending on BCa subtype. Currently, there is no clear understanding of MDSCs tailored to subtypes and metastatic sites in breast cancer. Here, we reviewed the biology and function of MDSCs revealed in BCa, focusing on metastasis and lipid metabolism, and discussed treatments targeting MDSCs. Understanding MDSC properties and function by BCa subtype and metastatic niche will be a prerequisite for taking the next step in subdividing BCa patients and providing customized treatment.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-24-0838
  12. J Immunother Cancer. 2025 Oct 13. pii: e012321. [Epub ahead of print]13(10):
    Envirotune-CAR-T: a hypoxia-responsive and glutamine-enhanced CAR-T cell therapy for overcoming tumor microenvironment-mediated suppression.
    Wenying Li, Jiannan Chen, Jiayi Li, Shuai Wang, Zhengliang Chen, Lianfeng Zhao, Yaoyao Zhao, Lili Gu, Jiaqi Liu, Yan Zhang, Xinhao Yang, Tianyu Chen, Zhigang Guo.
       BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in hematologic malignancies; however, its efficacy in solid tumors remains limited. A major barrier is the immunosuppressive tumor microenvironment (TME), which is characterized by hypoxia and nutrient deprivation, leading to impaired CAR-T cell proliferation, persistence, and cytotoxic function. To address these barriers, we designed a dual-regulatory CAR-T strategy that integrates hypoxia-responsive control with metabolic enhancement to improve therapeutic efficacy in solid tumors.
    METHODS: To overcome these barriers, we developed a next-generation CAR-T platform with dual adaptations targeting the metabolic and transcriptional constraints of the TME. Specifically, we engineered hypoxia-responsive regulatory elements derived from VEGF to drive sustained CAR expression under hypoxic conditions. Concurrently, we overexpressed the glutamine transporter SLC38A2 to enhance glutamine uptake and metabolic fitness in nutrient-deprived environments.
    RESULTS: Compared with conventional CAR-T cells, our engineered CAR-T cells exhibited superior antitumor activity under hypoxia and nutrient stress, with enhanced proliferation, elevated memory phenotype, and reduced exhaustion markers. Mechanistically, quantitative PCR demonstrated upregulation of glutamine metabolic and glycolytic pathways, while Seahorse assays confirmed enhanced oxidative phosphorylation and glycolysis. SLC38A2 knockout reversed these enhancements, highlighting its role in sustaining CAR-T metabolic fitness.
    CONCLUSION: Our findings establish SLC38A2 as a critical metabolic regulator that enhances CAR-T antitumor efficacy, providing a promising strategy to improve the durability and efficacy of CAR-T cell therapies in TME.
    Keywords:  Chimeric antigen receptor - CAR; Immunotherapy; Memory; Solid tumor; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2025-012321
  13. Mol Cell Biol. 2025 Oct 13. 1-14
    The Role of Tumor-Intrinsic HuR in Modeling the Pancreatic Tumor Microenvironment: Molecular Mechanisms and Therapeutic Opportunities.
    Katherine R Pelz, Kyle P Gribbin, Tess Sevetson, Jonathan R Brody.
      Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to therapy, due in part to the complex interplay between tumor cells and their microenvironment. Human antigen R (HuR/ELAVL1), a ubiquitously expressed RNA-binding protein, is emerging as an important regulator both of tumor-intrinsic and tumor-extrinsic pathways that govern PDAC progression. While the role of HuR in promoting cancer cell survival under stress is well established, recent studies reveal its broader role in shaping the tumor microenvironment (TME), including metabolic rewiring, stromal activation, angiogenesis, and immune modulation. In this review, we examine how tumor-intrinsic HuR drives epithelial-mesenchymal transition, stabilizes key transcripts involved in metabolic adaptation, and alters the tumor secretome to influence extracellular matrix deposition and fibroblast behavior. We further explore the role of HuR in regulating immune cell function and the immune landscape of PDAC. Notably, HuR-driven TME remodeling reinforces environmental stressors that further activate HuR, establishing a feed-forward loop that drives disease progression. These findings underscore HuR as a central regulator of the PDAC TME and therapeutic resistance, and thus, highlight its potential as a target in PDAC.
    Keywords:  ELAVL1; HuR; pancreatic ductal adenocarcinoma (PDAC); tumor microenvironment (TME)
    DOI:  https://doi.org/10.1080/10985549.2025.2557414
  14. Int J Mol Sci. 2025 Sep 24. pii: 9323. [Epub ahead of print]26(19):
    Exosomal miRNAs: Key Regulators of the Tumor Microenvironment and Cancer Stem Cells.
    Shuangmin Wang, Sikan Jin, Jidong Zhang, Xianyao Wang.
      Exosomes are lipid bilayer vesicles approximately 30-150 nm in diameter that serve as key mediators of intercellular communication. By transporting diverse bioactive molecules, including proteins and nucleic acids, they play a crucial role in tumor initiation and progression. Among their functional cargo, exosomal microRNAs (miRNAs) are central to epigenetic regulation and intercellular signaling, significantly influencing tumor biology. This review provides a comprehensive overview of the multifaceted roles of exosomal miRNAs in remodeling the tumor microenvironment (TME) and regulating cancer stem cells (CSCs). Specifically, exosomal miRNAs modulate various immune cells (such as macrophages, T cells, and NK cells) as well as cancer-associated fibroblasts (CAFs), thereby promoting immune evasion, angiogenesis, epithelial-mesenchymal transition (EMT), and metastatic progression. At the same time, they enhance CSC stemness, self-renewal, and therapeutic resistance, ultimately driving tumor recurrence and dissemination. Furthermore, exosome-mediated miRNA signaling acts as a critical force in malignant progression. Finally, we discuss the clinical potential of exosomal miRNAs as diagnostic and prognostic biomarkers, therapeutic targets, and vehicles for targeted drug delivery, highlighting their translational value and future directions in cancer research.
    Keywords:  CSCs; cancer; exosomes; miRNA
    DOI:  https://doi.org/10.3390/ijms26199323
  15. Mol Immunol. 2025 Oct 14. pii: S0161-5890(25)00240-8. [Epub ahead of print]187 198-209
    The metabolic regulation of tumor-associated macrophage reprogramming.
    Hao Fan, Dongxiao Lu, Xianyong Yin, Hao Sun, Zhihai Wang, Haohan Sun, Xiangyin Liu, Yuming Li, Zijian Zhou, Liang Chen, Yinyan Wang, Tao Xin.
      Tumor-associated macrophages (TAMs) are an essential component of the immune cells that infiltrate the tumor microenvironment (TME) and exhibit immunosuppressive functions. These macrophages exhibit significant phenotypic plasticity and heterogeneity, highlighting their capacity to adapt to various environmental signals. This adaptability facilitates polarization shifts between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. As tumors proliferate and metastasize, the TME progressively transforms into an immunosuppressive environment. Consequently, TAMs undergo metabolic reprogramming in pathways such as glucose, lipid, and amino acid metabolism, among others, which ultimately drive the establishment of an immunosuppressive phenotype. While TAMs do not strictly conform to the M1 and M2 classifications, they often exhibit characteristics resembling M2 macrophages, thereby promoting tumor growth via immunosuppression. This review aims to elucidate the metabolic reprogramming of TAMs and investigate how they maintain their immunosuppressive phenotype, highlighting potential avenues for metabolic therapies.
    Keywords:  Metabolic reprogramming; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.molimm.2025.10.006
  16. Research (Wash D C). 2025 ;8 0915
    Gene Signature-Based Drug Screening Reveals Ponatinib Enhances Immunotherapy Efficacy in Triple-Negative Breast Cancer by Reversing MDSC-Mediated Immunosuppressive Tumor Microenvironment.
    Qianyu Wang, Shasha Li, Yuan Wu, Xiankuo Yu, Yifei Dai, Yumei Wang, Lu Li, Ming Yang, Kequan Lin, Wei Shao, Haiyan Wang, Huili Wang, Guanbin Zhang, Dong Wang.
      The infiltration of myeloid-derived suppressor cells (MDSCs) is critical for the establishment of immunosuppressive tumor microenvironment (TME), yet no approved therapies specifically block it. Here, we employed a gene signature-based drug screening approach to identify potential agents for reversing MDSC-mediated immunosuppression in triple-negative breast cancer (TNBC). Transcriptomic analysis of 73,326 tumor samples and 190,588 single cells revealed C-X-C motif ligand 1 (CXCL1) and CXCL2 as the key gene signature of MDSC infiltration. Combining this gene signature with high-throughput sequencing-based high-throughput screening (HTS2), we identified ponatinib as a potential inhibitor of MDSC infiltration. By employing multiple preclinical models, we demonstrated that ponatinib blocks MDSC infiltration and reverses the immunosuppressive TME, thus inhibiting TNBC growth in a TME-dependent manner, and significantly enhances anti-programmed cell death-ligand 1 (PD-L1) immunotherapy efficacy. Mechanistically, ponatinib directly inhibits p38α kinase activity, reducing signal transducer and activator of transcription 1 (STAT1) phosphorylation at Ser727 and suppressing CXCL1 and CXCL2 expression in cancer cells, thereby blocking MDSC infiltration. Our findings establish ponatinib as a novel inhibitor of MDSC-mediated immunosuppressive TME and underscore its therapeutic potential in combination with immune checkpoint blockade for TNBC treatment.
    DOI:  https://doi.org/10.34133/research.0915
  17. Biochim Biophys Acta Rev Cancer. 2025 Oct 14. pii: S0304-419X(25)00220-3. [Epub ahead of print] 189478
    Role of macrophage PKM2 in inflammation and tumor progression and its targeted therapy.
    Yafei Li, Lingao Zhu, Lu Liu, Bo Li.
      Macrophages play a dual role of promoting or inhibiting in inflammation and tumor progression, highly dependent on the dynamic changes of M1/M2 polarization. In inflammation, M1/M2 polarization balance determines the outbreak of inflammation or tissue repair. In the tumor microenvironment, M1 tumor-associated macrophages (TAMs) exert both anti-tumor and pro-tumor effects, while M2 TAMs promote tumor progression. PKM2 regulates the M1/M2 polarization and cytokine secretion of macrophages through the pyruvate kinase activity of tetramers as well as the protein kinase activity and transcriptional co-activator function of dimers. This review summarizes the role and molecular mechanism of macrophage PKM2 in inflammation and tumor progression，highlighting its potential as a therapeutic target in inflammatory diseases and cancers. Macrophage PKM2 plays a promoting role in inflammation and tumor progression due to its dual regulatory characteristics of metabolism and immunity. It can not only meet the energy demands of macrophages through glycolytic metabolism, but also affect the immune response through enzyme activity-dependent and non-dependent mechanisms. The non-enzyme activity-dependent mechanism by which PKM2 regulates immune responses serves as a bridge connecting cellular metabolism and immune responses. The unresolved issues include the functional heterogeneity of macrophage PKM2 across different macrophage subtypes, its specific roles in lipid and amino acid metabolism, its contribution to tumor microenvironmental metabolic reprogramming, and PKM2-mediated interactions of macrophages with other cells.
    Keywords:  PKM2; inflammation; macrophage; targeted therapy; tumor
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189478
  18. Immunooncol Technol. 2025 Dec;28 101064
    Protein engineering to overcome limitations of key cytokines in cancer immunotherapy: current approaches and future perspectives.
    U Salazar, P Cioffi, B Taskoparan, I Moraga, S Mitra, J Vom Berg.
      Given their central role in immune regulation, cytokines have long been considered attractive therapeutic agents, particularly in cancer immunotherapy. Despite a strong preclinical and clinical rationale, only a limited number of cytokines have been approved for cancer immunotherapy to date, and their clinical use often remains limited to specialized centers. Here we briefly review the biological traits that make some of the most widely studied cytokines-specifically, interleukin (IL)-2, IL-15, and IL-12-attractive for immunotherapy and, conversely, the challenges encountered during their clinical translation. Focusing on these three cytokines in the context of systemic or local delivery, we highlight protein engineering strategies that address challenges to increase their therapeutic index, such as poor tolerability, short serum half-life, and pleiotropy. For systemic delivery, these strategies include the use of shielded cytokines and immunocytokines to elicit tissue context-dependent activity by taking advantage of unique characteristics of the tumor microenvironment (TME). Half-life extension domains to increase serum prevalence, partial agonism to restrict activity to intended effector cells, and cis-targeting are also discussed. For local administration, we review protein modifications intended to increase prevalence in the tumor, including increased size, adhesion to the extracellular matrix, targeting tumor-associated antigens, or targeting immune effector cells in the TME. Looking ahead, we anticipate the development of novel approaches such as reversible, context-dependent switches, and an increasing number of combinations of individual modifications.
    Keywords:  cytokine; immuno-oncology; interleukin; intratumoral; local administration; protein engineering
    DOI:  https://doi.org/10.1016/j.iotech.2025.101064
  19. Int Immunopharmacol. 2025 Oct 15. pii: S1567-5769(25)01638-8. [Epub ahead of print]167 115647
    Ferroptosis as a precise target for tumor-associated neutrophils: From molecular insights to targeted therapies.
    Danni Zhao, Minjie Guo, Yuting Zhang, Hele Liu, Xuanyin Ding, Xiao Yuan, Xu Wang.
      Ferroptosis is an iron-dependent form of regulated cell death characterized by the lethal accumulation of peroxidized lipids within cellular membranes and has emerged as a promising avenue in cancer therapy. Recent studies have indicated that pharmacologically induced ferroptosis can inhibit tumor progression; however, nonselective induction strategies often result in limited therapeutic efficacy because of a failure to account for the complex dynamics of the tumor microenvironment (TME). Neutrophils-the most abundant immune cells in humans-display remarkable phenotypic plasticity, adopting context-specific functions that can either promote or suppress tumor development. Their inherently high iron content renders them particularly vulnerable to ferroptosis, a process that is now recognized to contribute significantly to immunosuppression. This insight underscores the importance of incorporating neutrophil-related mechanisms into ferroptosis-based therapeutic strategies, both in terms of the tumor-promoting effects of neutrophil ferroptosis and their role in modulating tumor cell ferroptosis through iron metabolism reprogramming. This review highlights these dual mechanisms mediated by neutrophils and identifies potential therapeutic targets, offering new perspectives for enhancing ferroptosis-centered cancer treatments.
    Keywords:  Cancer therapy; Ferroptosis; Neutrophils
    DOI:  https://doi.org/10.1016/j.intimp.2025.115647
  20. Int J Mol Sci. 2025 Sep 25. pii: 9371. [Epub ahead of print]26(19):
    Enhanced Collagen Prolyl 4-Hydroxylase Activity and Expression Promote Cancer Progression via Both Canonical and Non-Canonical Mechanisms.
    Dalton Hironaka, Gaofeng Xiong.
      Collagens make up the main components of the extracellular matrix (ECM), and, in cancer, are often aberrantly secreted by both tumor cells and stromal cells in the tumor microenvironment (TME). Collagen prolyl 4-hydroxylase (C-P4H), an enzyme that hydroxylates proline into 4-hydroxyproline at the Y position of the collagen -X-Y-Gly- triplet motif, is essential for the stability of the mature collagen trimer and collagen secretion. In this review, we summarize the research on the structure and function of C-P4H, the regulation of C-P4H enzyme activity, and the role of overexpression of its α-subunit, P4HA1, in promoting cancer progression as well as its potential as a prognostic marker and therapeutic target. Overexpression of P4HA1 is displayed in almost all solid cancers, including breast, colorectal, and lung cancer, and is associated with cancer progression, worse response to therapy, and poorer patient survival. Characterization of P4HA1 overexpression has demonstrated links to key hallmarks of cancer, not only in the canonical collagen deposition role, but also in non-canonical functions, such as cell stemness, hypoxic response, glucose metabolism, angiogenesis, and modulation of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment. P4HA1 is thus an attractive target for developing novel targeted therapies to improve treatment response in many cancer types.
    Keywords:  collagen; prolyl 4-hydroxylase; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms26199371
  21. Int Dent J. 2025 Oct 15. pii: S0020-6539(25)03232-0. [Epub ahead of print]75(6): 103949
    Glycolytic Reprogramming in Oral Squamous Cell Carcinoma: Molecular Regulators and Natural Product-Based Therapies.
    Ji-Ae Shin.
      Oral squamous cell carcinoma (OSCC), the most common malignancy of the oral cavity, poses significant clinical challenges owing to late-stage diagnosis, frequent recurrence, and therapy resistance. Metabolic reprogramming, particularly the upregulation of aerobic glycolysis, is intricately associated with tumor progression, metastasis, and therapeutic failure. This metabolic alteration not only favors rapid cancer cell proliferation and promotes immune evasion but also results in the formation of a supportive tumor microenvironment (TME). This review synthesizes the current knowledge on the molecular regulators of glycolytic reprogramming in OSCC and elucidates their underlying mechanisms. We also delineated the glycolytic landscape of the OSCC tumor microenvironment, which encompasses cancer-associated fibroblasts (CAFs), CD4+ and CD8+ T cells, and tumor-associated macrophages (TAMs). Furthermore, we underscore the therapeutic potential of natural product-based strategies that target aerobic glycolysis in OSCC. A deeper understanding of these metabolic pathways may aid in the development of metabolism-targeted interventions for OSCC. This review also offers insights into how targeting glycolytic reprogramming, particularly with natural products, may enhance the efficacy of current chemotherapeutic and immunotherapeutic strategies for OSCC by overcoming resistance and reprogramming the TME.
    Keywords:  Aerobic glycolysis; Cancer metabolism; Metabolic regulators; Metabolic reprogramming; Natural products; Oral squamous cell carcinoma
    DOI:  https://doi.org/10.1016/j.identj.2025.103949
  22. Cancer Lett. 2025 Oct 11. pii: S0304-3835(25)00648-2. [Epub ahead of print]634 218076
    Tumor microenvironment and macroenvironment: A new perspective on holistic oncology.
    Qun Chen, Kuirong Jiang, Michael S Bronze, Min Li, Courtney W Houchen, Yuqing Zhang.
      The tumor microenvironment (TME) and tumor macroenvironment (TMaE) jointly shape cancer biology by linking local cellular niches with systemic host physiology. The TME provides the immediate soil for tumor initiation, progression, and therapy resistance, whereas the TMaE integrates metabolic, immune, neuroendocrine, microbial, and inflammatory signals that remodel local ecosystems. Recent advances highlight how systemic factors, including aging, energy imbalance, chronic inflammation, cachexia, and psychosocial stress, interact with extracellular matrix remodeling, vascular dynamics, and immune surveillance to influence tumor dormancy, metastatic reactivation, and therapeutic outcomes. However, the conceptual boundaries between TME and TMaE remain unclear, mechanistic insights are limited, and current models insufficiently capture local-systemic crosstalk. Future strategies integrating multi-omics, advanced imaging, and humanized models are essential to map this multidimensional interplay. A deeper understanding of TME-TMaE will be critical to refine precision oncology, advance preventive strategies, and design combinatorial therapies targeting both local and systemic cancer ecosystems. This review highlights the roles of the TME and TMaE in tumor initiation, progression, and heterogeneity, their interactions, and the clinical implications for classification, therapy, and prognosis.
    Keywords:  Immunity; Local-systemic crosstalk; Precise treatment; Tumor macroenvironment; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2025.218076
  23. J Hematol Oncol. 2025 Oct 13. 18(1): 86
    Targeting triple-negative breast cancer using cord-blood CD34⁺ HSPC-derived mesothelin-specific CAR-NKT cells with potent antitumor activity.
    Yan-Ruide Li, Xinyuan Shen, Yichen Zhu, Zhe Li, Ryan Hon, Yanxin Tian, Jie Huang, Annabel S Zhao, Nathan Y Ma, Catherine Zhang, David Lin, Karine Sargsyan, Yuan Yuan, Lili Yang.
       BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the lack of ER, PR, and HER2 expression. Its aggressive behavior, high degree of tumor heterogeneity, and immunosuppressive tumor microenvironment (TME) are associated with poor clinical outcomes, rapid disease progression, and limited therapeutic options. Although chimeric antigen receptor (CAR)-engineered T cell therapy has shown certain promise, its applicability in TNBC is hindered by antigen escape, TME-mediated suppression, and the logistical constraints of autologous cell production.
    METHODS: In this study, we employed hematopoietic stem and progenitor cell (HSPC) gene engineering and a feeder-free HSPC differentiation culture to generate allogeneic IL-15-enhanced, mesothelin-specific CAR-engineered invariant natural killer T (Allo15MCAR-NKT) cells.
    RESULTS: These cells demonstrated robust and multifaceted antitumor activity against TNBC, mediated by CAR- and NK receptor-dependent cytotoxicity, as well as selective targeting of CD1d+ TME immunosuppressive cells through their TCR. In both orthotopic and metastatic TNBC xenograft models, Allo15MCAR-NKT cells demonstrated potent antitumor activity, associated with robust effector and cytotoxic phenotypes, low exhaustion, and a favorable safety profile without inducing graft-versus-host disease.
    CONCLUSIONS: Together, these results support Allo15MCAR-NKT cells as a next-generation, off-the-shelf immunotherapy with strong therapeutic potential for TNBC, particularly in the context of metastasis, immune evasion, and treatment resistance.
    Keywords:  Allogeneic CAR-NKT cells; Allogeneic cell therapy; Allorejection; CRISPR-Cas9 gene editing; HLA ablation; Mesothelin-targeting CAR (MCAR); Metastatic model; Multiple tumor targeting mechanism; Off-the-shelf; Orthotopic model; Potent antitumor activity; Triple-negative breast cancer (TNBC); Tumor microenvironment (TME); Tumor-associated macrophage (TAM)
    DOI:  https://doi.org/10.1186/s13045-025-01736-9
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