bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–08–10
28 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Multifaceted role of myeloid-derived suppressor cells in colorectal cancer.
  2. Focusing on the interplay between tumor-associated macrophages and tumor microenvironment: from mechanism to intervention.
  3. Myeloid-Derived Suppressor Cells: Orchestrators of Tumor Immune Evasion and Therapeutic Vulnerabilities.
  4. Metabolic insights into TAMs and the tumor immune microenvironment: Regulatory mechanisms and therapeutic interventions.
  5. Advances in the regulation of macrophage polarization by the tumor microenvironment.
  6. [Next-generation CAR gene-modified cell therapy: overcoming resistance and exploring novel applications].
  7. Haoya Wang Et Al.: Circadian Rhythm Disruption Promotes Tumor Progression Through Upregulated Glycolysis.
  8. The role of tissue factor in the tumor microenvironment and targeted therapy.
  9. Targeting CSC-immune cell crosstalk to overcome chemoresistance and enhance immunotherapy efficacy.
  10. Precision-cut tumor tissue slices, a novel tool to study the tumor microenvironment interactions with chimeric antigen receptor (CAR) T cells.
  11. Unlocking the Immune Response in ALK-Rearranged Lung Adenocarcinoma.
  12. Histone lactylation: a new target for overcoming immune evasion and therapy resistance.
  13. The dual role of CD36 in cancer: from lipid metabolism to tumor microenvironment regulation.
  14. Cancer-associated fibroblasts in hepatocellular carcinoma: origins, heterogeneity, and therapeutic implications.
  15. Cancer-associated fibroblasts: dual roles from senescence sentinels to death regulators and new dimensions in therapy.
  16. Research progress on the interaction between glucose metabolic reprogramming and lactylation in tumors.
  17. Actin-modulated nuclear shape controls adaptive reprogramming in cancer-associated fibroblasts.
  18. Music therapy in modulating immune responses and enhancing cancer treatment outcomes.
  19. Immunomodulation of the Breast Cancer Microenvironment by Tumor-Derived Exosomes: Implications for Immunotherapy.
  20. Tumor-derived small extracellular vesicles reprogram sensory nerves to drive immunosuppression in the tumor microenvironment.
  21. Metabolic checkpoints in immune cell reprogramming: rewiring immunometabolism for cancer therapy.
  22. Editorial: Microbiota homeostasis and metabolic reprogramming in cancer development and digestive diseases.
  23. Immunosuppressive cells in acute myeloid leukemia: mechanisms and therapeutic target.
  24. Fatty acid in the tumor microenvironment: perspectives for immunotherapy.
  25. Recent progress in the study of exosomes in the gastric cancer immune microenvironment.
  26. Alveolar macrophages maintain tissue localization and gain enhanced anti-tumor activity in Lewis lung carcinoma-reprogrammed lung microenvironment.
  27. P2 Purinergic Receptors in Tumor Immunity.
  28. Novel Insight into the Multiple Biological Characteristics of Polyamines in the Gut: From Structure to Function.
  1. Int Immunopharmacol. 2025 Aug 02. pii: S1567-5769(25)01264-0. [Epub ahead of print]163 115274
    Multifaceted role of myeloid-derived suppressor cells in colorectal cancer.
    Jiajia Zhang, Jingyao Lian, Ningning Li, YueYing, Gang Wu.
      Crosstalk between cancer cells and the immune system is an important determinant of cancer progression. The immune microenvironment of colorectal cancer (CRC) is a complex and heterogeneous system, consisting of massive infiltrations of myeloid cells and lymphocytes that remodel the tumor microenvironment (TME) through the secretion of cytokines, growth factors and proteases to promote or inhibit progression of CRC. Dendritic cells (DCs) and macrophages sense invading microorganisms and regulate the differentiation of inflammatory lymphocytes, further recruiting subsets of myeloid cells into the local intestinal tissue. Of these, Myeloid-derived suppressor cells (MDSCs), one of the most important types of tumor-promoting immune cells, are a diverse population of myeloid cells that strongly suppress antitumor immune responses. Accumulating evidence suggests that MDSCs also play a distinct but crucial role during inflammation-dependent CRC development in patients with inflammatory bowel disease and impede novel CRC immunotherapies. Consequently, MDSCs have emerged as one of the most attractive targets in the antitumor immune axis. This review focuses on the emerging insights into the complex regulatory network of MDSCs in CRC development, and the potential advantages of therapeutic targeting of MDSCs. We summarize the origin, development, differentiation characteristics and known functions of MDSCs. In addition, we describe potential therapeutic strategies based on MDSCs that may have the potential to improve the efficacy of cancer therapies in the future.
    Keywords:  Colitis-associated cancer; Colorectal cancer; Immune microenvironment; Immunotherapy; Inflammatory bowel disease; Myeloid-derived suppressor cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2025.115274
  2. Theranostics. 2025 ;15(15): 7378-7408
    Focusing on the interplay between tumor-associated macrophages and tumor microenvironment: from mechanism to intervention.
    Hancheng Wu, Jing Li, Ruilin Yao, Jing Liu, Lili Su, Wenjie You.
      Immunotherapy has generated promising outcomes in cancer treatment; however, therapeutic responses are hampered by immunosuppression in the tumor microenvironment (TME). This has resulted in increased study of key immune cells in the TME as therapeutic interventions. Tumor-associated macrophages (TAMs), a major component of infiltrating immune cells in the TME, display high plasticity, largely dependent on cues received from their surroundings. Although significant progress in metabolomics and single-cell omics has unraveled the metabolic and functional heterogeneity of TAMs across several types of cancer, the development of TAM-targeted therapy remains challenging. In the present review, the crosstalk between TAMs and other components in TME, such as tumor cells, immune cells, cancer-associated fibroblasts, and extracellular matrix is highlighted. Additionally, updated insights into the origin, heterogeneity, and metabolic reprogramming of TAMs are discussed, and relevant approaches of targeting TAMs in clinical investigations are summarized. The present review provides a deeper understanding of TAMs within the microenvironment network, aimed at identifying candidate targets to improve cancer immunotherapy.
    Keywords:  cancer immunotherapy; heterogeneity; interaction; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.7150/thno.113727
  3. Mol Cancer Res. 2025 Aug 04.
    Myeloid-Derived Suppressor Cells: Orchestrators of Tumor Immune Evasion and Therapeutic Vulnerabilities.
    Ziyu Wang, Xiaoping Du, Xiangxue Xing, Wenjing Xie, Haina Xin, Wan Liu.
      Myeloid-derived suppressor cells (MDSCs) are characterized by abnormal phenotypes, high heterogeneity, and immunosuppressive function. MDSCs are critical components in the tumor immune microenvironment, contributing to cancer progression by inhibiting T cells, B cells, natural killer cells, and dendritic cells, while promoting regulatory T cells, tumor-associated macrophages, and helper T cell 17. Beyond immune suppression, MDSCs facilitate tumor angiogenesis, tumor cell stemness, epithelial-mesenchymal transition, and pre-metastatic niche formation. Current therapeutic strategies targeting MDSCs include depletion, functional inhibition, induction of differentiation, and disruption of MDSC recruitment and activation. Various therapeutic agents-including chemotherapeutics, monoclonal antibodies, small-molecule inhibitors, and natural compounds-have shown efficacy in modulating MDSC activity. Combining MDSC-targeted therapy with existing immunotherapies, such as immune checkpoint inhibitors, may further improve anti-tumor responses.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-25-0251
  4. Biochim Biophys Acta Rev Cancer. 2025 Aug 05. pii: S0304-419X(25)00153-2. [Epub ahead of print] 189411
    Metabolic insights into TAMs and the tumor immune microenvironment: Regulatory mechanisms and therapeutic interventions.
    Lei Yang, Yingying Shao, Zewen Zhang, Yunfei Li, Fang Wang, Haiyang Yu.
      Tumor-associated macrophages (TAMs) are pivotal regulators of the tumor immune microenvironment exhibiting a dual role in tumor therapy by functioning as both pro-tumorigenic effectors and anti-tumor agents. Tumor cells reprogram macrophages towards the pro-tumorigenic M2 phenotype through the induction of signaling molecules and manipulation of metabolic pathways. Recent evidence indicates that the interplay between TAM functional polarization and metabolic reprogramming profoundly influences anti-tumor immunity across multiple dimensions. TAMs, in turn, collectively modulate the immunosuppressive niche via a complex interaction network involving dynamic metabolite exchange, immune checkpoint signaling, and sensing of the physical microenvironment. In this review, we integrate current understanding of TAM metabolic networks, elucidate key mechanisms by which they remodel the immunosuppressive microenvironment through metabolic crosstalk, and outline emerging therapeutic strategies targeting TAMs to overcome current treatment limitations.
    Keywords:  Metabolic crosstalk; Metabolic reprogramming; Targeted therapy; Tumor microenvironment (TME); Tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189411
  5. Discov Oncol. 2025 Aug 06. 16(1): 1487
    Advances in the regulation of macrophage polarization by the tumor microenvironment.
    Minzhi Peng, Yuan Zhu, Yi Hu, Jianping Wen, Weiguo Huang.
      The tumor microenvironment (Tumor Microenvironment, TME) is a core regulatory factor in the occurrence, development, and treatment resistance of tumors. Macrophages, as key immune cell components in the TME, have a profound impact on the tumor process (Visser and Joyce in Cancer Cell 41:374-403, 2023). This review aims to systematically elucidate the characteristics and functional differences of macrophage polarization into M1 and M2 phenotypes within the TME. Additionally, it endeavors to dissect the regulatory mechanisms by which metabolic products, cytokines, and extracellular matrix components secreted by tumor cells modulate macrophage polarization (Wang et al. in Mol Cancer 23:268, 2024). Moreover, the metabolic reprogramming of tumorassociated macrophage (TAM) is a core mechanism for their functional shift, and intervening in metabolic pathways holds promise for reprogramming TAMs to inhibit tumor progression (Jin et al. in Nat Cancer 6:239-252, 2025). Within the TME, macrophages can be polarized into classically activated M1 and alternatively activated M2 types (Ge and Wu in Zhongguo Fei Ai Za Zhi 26:228-237, 2023). Accumulating evidence indicates that classically activated M1 macrophages orchestrate anti-tumor immunity by secreting pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-12 (IL-12), which collectively activate cytotoxic T lymphocyte responses, induce tumor cell apoptosis, and enhance immune surveillance (Luo et al. in Front Immunol 15:1352946, 2024). In contrast, M2 macrophages are induced in the TME and promote tumor angiogenesis, immune evasion, tumor cell proliferation, and metastasis by secreting factors such as vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β) (Wang et al. in NPJ Precis Oncol 8:31, 2024). Therefore, in-depth research on the mechanisms of macrophage polarization in the tumor microenvironment provides an important basis for developing new tumor immunotherapy strategies and has significant clinical translational value.
    Keywords:  Immune cells; Macrophages; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12672-025-03258-9
  6. Rinsho Ketsueki. 2025 ;66(7): 679-686
    [Next-generation CAR gene-modified cell therapy: overcoming resistance and exploring novel applications].
    Reona Leo Sakemura.
      In recent years, chimeric antigen receptor (CAR)-engineered cellular therapy has brought remarkable advancements in cancer immunotherapy and autoimmune disease treatment. CAR T-cell therapy has demonstrated high efficacy in multiple myeloma (MM), but its durability is limited due to immune suppression within the tumor microenvironment (TME). This study elucidates how cancer-associated fibroblasts (CAFs) impair BCMA CAR T-cell function, and describes development of dual-specific CAR T-cells targeting CAFs. The results showed that CAFs promoted CAR T-cell exhaustion via TGF-β, PD-L1, IL-10, and the FAS/FASL pathway. BCMA-FAP and BCMA-CS1 CAR T cells exhibited enhanced cytotoxicity against MM cells and CAFs, overcoming TME-mediated suppression. E-cadherin-targeting CAR MSCs (Ecad CAR-MSCs) to address graft-versus-host disease (GvHD) were also developed for this study. These CAR MSCs significantly reduced GvHD by selectively accumulating in the intestinal epithelium, suppressing T-cell activation via IL-10 and galectin-9 while promoting Treg induction. These findings suggest that CAF-targeting dual-specific CAR T cells enhance the efficacy of MM immunotherapy, while Ecad CAR-MSCs offer a novel approach to treating GvHD. These approaches hold promise for clinical translation to improve outcomes in cellular therapy.
    Keywords:  CAR T-cell therapy; CAR-MSC; GvHD; Tumor microenvironment
    DOI:  https://doi.org/10.11406/rinketsu.66.679
  7. Cancer Med. 2025 Aug;14(15): e71138
    Haoya Wang Et Al.: Circadian Rhythm Disruption Promotes Tumor Progression Through Upregulated Glycolysis.
    Haoya Wang, Di Wu, Jie Li, Binghe Zhao, Lu Liu, Xinxin Wang.
       BACKGROUND: Aberrant activation of glycolysis (Warburg effect) constitutes a key metabolic reprogramming feature in malignant tumors, serving as a critical mechanism facilitating tumor development. Within the tumor microenvironment, this glycolytic reprogramming emerges in diverse cellular components, including cancer cells, immune cells (e.g., myeloid-derived suppressor cells and tumor-associated macrophages), and fibroblasts, thereby establishing a microenvironment that promotes tumor invasion and metastasis. Recent studies have revealed that the endogenous circadian system orchestrates glycolysis processes through multiple pathways, where circadian rhythm disruption frequently manifests as upregulated glycolysis with pro-tumorigenic consequences.
    METHODS: This review summarizes the specific mechanisms through which circadian rhythm disruption regulates the reprogramming of glycolytic metabolism in the tumor microenvironment. Emerging chronotherapeutic strategies focus on targeting glycolytic pathways.
    CONCLUSIONS: The reprogramming promotes enhanced glycolysis, ultimately accelerating tumor progression. Combination therapy with glycolysis inhibitors has the potential to further improve efficacy when optimized for time. Future research should prioritize unraveling the complex interplay between circadian rhythms, glycolysis, and the tumor microenvironment to advance more effective therapeutic interventions.
    Keywords:  aerobic glycolysis (Warburg effect); chronotherapy; circadian rhythm; glycolytic inhibitors; tumor microenvironment
    DOI:  https://doi.org/10.1002/cam4.71138
  8. Biochim Biophys Acta Rev Cancer. 2025 Aug 05. pii: S0304-419X(25)00151-9. [Epub ahead of print] 189409
    The role of tissue factor in the tumor microenvironment and targeted therapy.
    Ying Yan, Yifan Li, Dan Zou, Huanhuan Ma, Hao Chen.
      Tissue factor (TF) serves as a pivotal initiator of coagulation and has been extensively acknowledged for its substantial involvement in cancer progression and metastasis. Recent evidence suggests that targeting TF can enhance the infiltration of immune effector cells, thereby reshape the tumor microenvironment (TME). Despite these advancements, a comprehensive review of TF's role within the TME has yet to be conducted. This review uniquely synthesizes emerging evidence on TF-mediated immunosuppression mechanisms and evaluates cutting-edge targeting strategies to overcome therapy resistance.
    Keywords:  Immunotherapy; Tissue factor; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189409
  9. Front Immunol. 2025 ;16 1620807
    Targeting CSC-immune cell crosstalk to overcome chemoresistance and enhance immunotherapy efficacy.
    Guanxiao Yu, Jianbao Gong.
      Cancer stem cells (CSCs) are a subpopulation of tumor cells that play crucial roles in driving tumor recurrence, metastasis, and resistance to therapies, including chemotherapy and immunotherapy. Growing evidence suggests that interactions between CSCs and immune cells, particularly tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, create a supportive tumor microenvironment conducive to immune evasion and chemoresistance. Understanding these intricate crosstalk mechanisms, mediated via cytokines, exosomes, and metabolic intermediates, is crucial for the development of effective therapeutic strategies. Here, we comprehensively review recent progress on CSC-immune cell crosstalk, highlighting key signaling pathways and molecular targets. Furthermore, we discuss promising clinical strategies combining conventional therapies with interventions targeting CSC-immune interactions, aiming to enhance immunotherapy efficacy and overcome therapeutic resistance in cancer patients.
    Keywords:  CSC-immune crosstalk; cancer stem cells (CSCs); immune evasion; therapy resistance; tumor immune microenvironment (TIME)
    DOI:  https://doi.org/10.3389/fimmu.2025.1620807
  10. PLoS One. 2025 ;20(8): e0327322
    Precision-cut tumor tissue slices, a novel tool to study the tumor microenvironment interactions with chimeric antigen receptor (CAR) T cells.
    Valeria Durante, Alina Wittwer, Benjamin Theek, Manuel Martinez-Osuna, Emmanuel Donnadieu, Olaf Hardt, Dominik Eckardt, Andreas Bosio, Sonja Schallenberg, Christoph Herbel.
      Up until present day, chimeric antigen receptor (CAR)-T cell therapy has only been approved for hematological malignancies, as CAR-T cells do not show comparable efficacy in solid tumors. Therefore, understanding the features of the tumor microenvironment (TME), is key to improve efficacy of adoptive cell therapies (ACTs) against solid tumors. In this context, robust workflows, which dissect the complex interactions between CAR-T cells and the TME are still lacking. To address this need, we have established an ex vivo workflow co-culturing tissue slices from patient tumor resections with CAR-T cells. The workflow is composed of assessing several complementary attributes, such as cytokine release via flow cytometry, quantification of cell infiltration into the tumor and assessment of the regions of the tissue slice the CAR-T cell infiltrate into by using the MACSima™ imaging cyclic staining technology. Using this workflow it is possible to observe the behavior of CAR-T cells within the tumor and its TME, their infiltration into distinct tumor compartments, as well as to dissect the underlying molecular mechanisms that drive T cell migration, thanks to MACSima™ multiplexing technology and its ability to image several markers at the same time. Assessment of ovarian carcinoma tissue slices revealed substantial release of specific cytokines and increased infiltration of T cells in the tumor areas when CAR-T cells were added to the tissue slices as compared to non-engineered T cells. The establishment of this novel approach will enable researchers to better characterize the interaction between CAR-T cells and the TME. Tissue slices present an intrinsic heterogeneity, which is indeed an advantage compared to other in vitro models but can turn itself into complex results interpretation. Therefore, we recommend that any conclusion derived from this assay should be verified with complementary models.
    DOI:  https://doi.org/10.1371/journal.pone.0327322
  11. Cancer Immunol Res. 2025 Aug 08. OF1-OF2
    Unlocking the Immune Response in ALK-Rearranged Lung Adenocarcinoma.
    Antonio Vitale, Emilio Bria.
      Anaplastic lymphoma kinase-rearranged lung adenocarcinoma (ALK+ LUAD) is currently considered an immune-resistant disease, yet underlying biological mechanisms are largely unknown. In this issue, Arai and colleagues analyzed the tumor microenvironment (TME) in ALK+ LUADs, identifying a myeloid cell-dominant immunosuppressive TME, primarily driven by IL6 secretion. Dual anti-IL6R/anti-PD-L1 treatment resulted in robust antitumor effect in mouse models, restoring immune sensitivity and tumor control. These findings highlight a promising therapeutic approach to enhance the efficacy of PD-(L)1 inhibitors by reverting TME-mediated immune resistance, reshaping the role of immunotherapy in ALK+ LUADs. See related article by Arai et al., p. XX .
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0624
  12. Med Oncol. 2025 Aug 02. 42(9): 399
    Histone lactylation: a new target for overcoming immune evasion and therapy resistance.
    Fatemeh Ghadyani, Pouyan Zandi, Soudeh Ghafouri-Fard.
      While metabolic reprogramming in cancer is well-documented, the epigenetic consequences of lactate accumulation-particularly histone lactylation-remain underexplored as a unifying mechanism driving immune evasion and therapy resistance. This review synthesizes emerging evidence that lactylation remodels the tumor microenvironment (TME) by polarizing macrophages, exhausting T cells, and stabilizing oncogenic transcripts. We highlight the dual roles of lactylation as both a metabolic sensor and a mediator of immunosuppression, underscoring its potential as a therapeutic target. Unresolved questions, such as context-dependent effects of specific lactylation sites (e.g., H3K18la and H3K9la) and the interplay with other post-translational modifications, are critically evaluated. We also propose strategies to exploit lactylation pathways for combination therapies.
    Keywords:  Cancer; Histone lactylation; Immune escape; Therapy resistance
    DOI:  https://doi.org/10.1007/s12032-025-02940-w
  13. Mol Biol Rep. 2025 Aug 02. 52(1): 787
    The dual role of CD36 in cancer: from lipid metabolism to tumor microenvironment regulation.
    Yixuan Yao, Yanyuan Fang, Bin Yuan, Jing Yang.
      CD36, a class B scavenger receptor dynamically localizing to both plasma and intracellular organelle membranes, plays a crucial role in lipid metabolism regulation. In cancer biology, CD36 exhibits a context-dependent dual role, functioning as either a tumor suppressor or a tumor promoter upon cellular context and tumor microenvironment (TME). Within tumors, CD36 cooperates with autophagy to regulate tumorigenesis, largely through modulation of the TME. The central role of CD36 in regulating lipid homeostasis, along with emerging evidence of its involvement in cancer progression, highlights its therapeutic potential in cancer. This review examines multifaceted roles of CD36 in cancer, focusing on its contributions to dysregulated lipid metabolism, metastasis, dissemination, immune evasion, and therapeutic resistance.
    Keywords:  CD36; Cancer; Immune cells; Lipid metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s11033-025-10885-6
  14. Front Immunol. 2025 ;16 1620075
    Cancer-associated fibroblasts in hepatocellular carcinoma: origins, heterogeneity, and therapeutic implications.
    Xin Shi, Weixiong Zhu, Jianpeng Zhang, Chuanlei Fan, Jing Zhang.
      Hepatocellular carcinoma (HCC) is a globally prevalent malignancy. This disease often progresses rapidly, resulting in many patients being diagnosed at a late stage, making early detection and intervention a major clinical challenge. Postoperative recurrence and metastasis rates remain significantly high, and no effective prevention strategies are currently available. Cancer-associated fibroblasts (CAFs) are essential components in the reorganization of the tumor microenvironment (TME), as they can modulate cancer cell proliferation, migration, invasion, and chemoresistance through diverse mechanisms or signaling pathways, including the release of cytokines, remodeling of the extracellular matrix, and the evasion of the immune response. This review offers a detailed overview of the cellular origins, subtype diversity, and functional differences among CAFs. In addition, it depicts the expression profiles of key markers in various CAF subtypes and clarifies essential signaling pathways and mechanisms of CAFs. Additionally, we discuss current and future therapeutic strategies targeting CAFs in the context of HCC. This review provides critical insights into future studies on novel therapeutic approaches for CAFs.
    Keywords:  cancer-associated fibroblasts (CAFs); hepatocellular carcinoma (HCC); immune evasion; therapeutic resistance; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2025.1620075
  15. Front Immunol. 2025 ;16 1635771
    Cancer-associated fibroblasts: dual roles from senescence sentinels to death regulators and new dimensions in therapy.
    Guixiang Ruan, Xiang Wang, Huiyi Ou, Duancheng Guo.
      Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment (TME), playing a pivotal role in tumor initiation, progression, and therapeutic resistance. This review explores the dual roles of CAFs in regulating tumor cell senescence and cell death, elucidating their mechanisms in inducing cellular senescence, shaping an immunosuppressive milieu, and modulating cell death pathways. CAFs promote tumor progression by secreting pro-inflammatory factors and extracellular matrix (ECM) components, while also contributing to metabolic reprogramming, immune evasion, and therapy resistance, thereby influencing anti-cancer treatment efficacy. Studies indicate that the heterogeneity and plasticity of CAFs determine their distinct functions across various tumor types. Consequently, precision-targeted therapeutic strategies against CAFs, including the elimination of senescent CAFs, inhibition of the senescence-associated secretory phenotype (SASP), and disruption of CAF-mediated cell death evasion mechanisms, have emerged as promising directions in cancer research. This review provides a comprehensive analysis of CAFs functions and their potential as therapeutic targets, offering valuable insights into the development of novel anti-cancer strategies.
    Keywords:  SASP; TME; cancer-associated fibroblasts; cell death; cell senescence
    DOI:  https://doi.org/10.3389/fimmu.2025.1635771
  16. Front Immunol. 2025 ;16 1595162
    Research progress on the interaction between glucose metabolic reprogramming and lactylation in tumors.
    Yi Yang, Yi Wu, Hui Chen, Zehai Xu, Ruisi Lu, Sijie Zhang, Rui Zhan, Qinghua Xi, Yunfeng Jin.
      Glucose metabolic reprogramming describes the alterations in intracellular metabolic pathways in response to variations in the body's internal environment. This metabolic reprogramming has been the subject of extensive research. The primary function is to enhance glycolysis for rapid ATP production, even with sufficient oxygen, leading to a significant accumulation of lactic acid, which subsequently affects the functions of tumor cells and immune cells within TME. Lactylation represents a newly identified post-translational modification (PTM) that occurs due to lactate accumulation and is observed in various proteins, encompassing both histone and non-histone types. Lactylation alters the spatial configuration of proteins, influences gene transcription, and thereby regulates gene expression. This modification serves as a significant epigenetic regulatory factor in numerous diseases. Glucose metabolic reprogramming and lactylation are intricately linked in the process of tumorigenesis. Glucose reprogramming activates essential enzymes, including hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA), through transcription factors such as HIF-1α and c-Myc, thereby enhancing glycolysis and lactate accumulation. Lactate functions as a metabolite and signaling molecule, acting as a substrate for lactylation facilitated by histone acetyltransferases such as CBP/p300. This epigenetic modification inhibits antitumor immunity through the upregulation of oncogenic signaling pathways, the induction of M2-type macrophage polarization, and the dysfunction of T-cells. Glucose metabolic reprogramming not only influences lactate synthesis but also provides sufficient substrates for lactate modification. The two factors jointly affect gene expression and protein function, acidify the tumor microenvironment, regulate immune evasion, and promote carcinogenesis. This review systematically details the mechanisms of lactylation and glucose metabolic reprogramming, their impacts on immune cells within the tumor microenvironment, and their interrelations in tumor progression, immunity, and inflammation.
    Keywords:  glucose metabolic reprogramming; immune cells; lactate; lactylation; macrophage; posttranslational modification; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1595162
  17. bioRxiv. 2025 Jul 23. pii: 2025.07.19.665630. [Epub ahead of print]
    Actin-modulated nuclear shape controls adaptive reprogramming in cancer-associated fibroblasts.
    Jie Wang, Bruna da Silva Soley, Yao Xiao, Lindsey G Siegfried, Linli Zhou, Mingang Xu, Sarah E Millar, Thomas Andl, Yuhang Zhang.
      Cancer-associated fibroblasts (CAFs) adapt to external cues such as therapeutic agents and extracellular matrix (ECM) stiffness in the tumor microenvironment (TME) through a reprogramming process. Here, we show that BRAF inhibitors (BRAFis) drive accumulation of nuclear β-catenin in CAFs by inducing actin-mediated deformation of the nucleus. Exposure to stiff substrates can also lead CAFs to undergo cytoskeletal reorganization and exert forces on the nucleus, allowing β-catenin to enter the nucleus and reprogram its transcriptional activities. Mechanistically, BRAFi accelerates RAS-dependent RAF kinase transactivation by binding to the BRAF and CRAF kinase domains, accelerating BRAF and CRAF homo and heterodimerization and phosphorylation. Subsequently, RAF activation initiates downstream ERK signaling, which simultaneously inactivates GSK-3β and stimulates Rho kinase (ROCK) signaling. Notably, ablating RAS and RAF isoforms as well as pharmacological blockade of ROCK activity effectively suppressed BRAFi-induced nuclear deformation and β-catenin entry in CAFs, further confirming that the ROCK-cytoskeleton axis mediates BRAFi-driven RAF activation and nuclear import of β-catenin for reprogramming. Thus, ROCK-regulated actin polymerization is a master CAF response pathway that can be stimulated by external signals to reprogram the transcriptional activity of CAFs by enhancing nuclear β-catenin transport through a noncanonical mechanical mechanism.
    DOI:  https://doi.org/10.1101/2025.07.19.665630
  18. Front Immunol. 2025 ;16 1639047
    Music therapy in modulating immune responses and enhancing cancer treatment outcomes.
    Ye Fu, Ke Wu, Jiajia Zhuang, Yisheng Chen, Lina Jia, Zhiwen Luo, Rong Sun.
      Music therapy, an intersection of art and science, is gaining recognition as a complementary approach in cancer care. This review systematically explores its mechanisms, applications, and effectiveness, with a focus on its impact on the tumor microenvironment (TME), particularly immune signaling and inflammation at single-cell resolution. Evidence shows that music therapy alleviates psychological symptoms-such as anxiety and depression-and physical discomforts including pain, fatigue, and nausea. Beyond symptomatic relief, it also modulates immune responses, especially in immune cell populations that influence tumor-associated inflammation and cancer progression. Advances in single-cell technologies may begin to explain how music therapy modulates immune signaling pathways within the TME, potentially enhancing treatment efficacy.Despite its non-invasive, cost-effective nature and high patient acceptability, music therapy remains underutilized in oncology. Further large-scale studies are needed to elucidate its molecular mechanisms, refine intervention models, and validate its role in immune modulation. As research advances, music therapy holds promise as a valuable component of integrative oncology, supporting patient recovery and immune homeostasis.
    Keywords:  cancer; immune modulation; inflammation; integrative oncology; music therapy; neuroimmune interaction; single-cell resolution; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1639047
  19. Cancer Invest. 2025 Aug 07. 1-24
    Immunomodulation of the Breast Cancer Microenvironment by Tumor-Derived Exosomes: Implications for Immunotherapy.
    Sepideh Maralbashi, Cynthia Aslan, Houman Kahroba, Mahsa Javadian, Najibeh Shekari, Elham Safarzadeh, Farhad Salari, Tohid Kazemi.
      Exosomes are 30-150 nm extracellular vesicles released by nearly all cells, including tumor cells. Cancer cell-derived exosomes carry various molecular contents - proteins, mRNAs, microRNAs- that are transferred to recipient cells, contributing to cancer development, angiogenesis, metastasis, and immune evasion. Breast cancer-derived exosomes (BEXs) express multiple immunomodulatory molecules, particularly the ectoenzymes CD39 and CD73, which catalyze the conversion of adenosine triphosphate (ATP) into adenosine. Adenosine then binds its receptors (ADORs) to transmit immunosuppressive signals. BEXs also express immune checkpoint molecules such as programmed death ligand 1 (PD-L1), CD200, and CD47 that suppress immune surveillance through interaction with programmed cell death protein 1 (PD-1), CD200R, and signal-regulatory protein alpha (SIRPα), respectively. Notably, PD-L1 appears to be more enriched on exosomes than on tumor cell surfaces, underscoring the pivotal role of BEXs in immune regulation. Given their influence on several hallmarks of cancer, BEXs are promising candidates for future diagnostic and therapeutic strategies, particularly in immunotherapy.
    Keywords:  Breast cancer; CD39; CD73; PD-L1; Tumor-derived exosome
    DOI:  https://doi.org/10.1080/07357907.2025.2529878
  20. Sci Signal. 2025 Aug 05. 18(898): eady6769
    Tumor-derived small extracellular vesicles reprogram sensory nerves to drive immunosuppression in the tumor microenvironment.
    Leah Boyd, Jeremy C Borniger.
      Neuroimmune cross-talk is emerging as an important regulator of tumor growth and progression in cancers beyond the central nervous system. In this issue of Science Signaling, Restaino et al. demonstrate that tumor-derived small extracellular vesicles promote tumor growth by altering the secretory profile of infiltrating sensory neurons, generating a feed-forward loop that ultimately drives immunosuppression in the tumor microenvironment.
    DOI:  https://doi.org/10.1126/scisignal.ady6769
  21. Mol Cancer. 2025 Aug 02. 24(1): 210
    Metabolic checkpoints in immune cell reprogramming: rewiring immunometabolism for cancer therapy.
    Yingying Lv, Zongshang Li, Shutong Liu, Zhaokai Zhou, Jinling Song, Yuhao Ba, Siyuan Weng, Anning Zuo, Hui Xu, Peng Luo, Quan Cheng, Chuhan Zhang, Jingyuan Ning, Yukang Chen, Yuyuan Zhang, Zaoqu Liu, Xinwei Han.
      Immune cell metabolism plays a pivotal role in regulating cellular proliferation, differentiation, and functional responses, collectively shaping immune responses within the tumor microenvironment (TME). Recent advancements increasingly highlight diverse metabolic phenotypes of immune cells and their complex interplay with tumor dynamics. Immune cell metabolism exhibits remarkable plasticity, enabling metabolic networks to finely tune immune cell behaviors in response to external stimuli. Furthermore, a strong correlation between metabolic profiles and immune cell fate, activation, and function has been repeatedly delineated in immunometabolism. Consequently, targeting the metabolic networks, referred to as metabolic checkpoints, to reprogram immune cell phenotypes and bolster antitumor immunity holds significant promise for clinical translation. This review summarizes the latest developments in multifaceted metabolic checkpoints, with a focus on how metabolic checkpoints modulate immunological consequences and cancer progression. Lastly, potential strategies for targeting metabolic checkpoints are explored to inspire innovative approaches in immunotherapy.
    Keywords:  Cancer immunotherapy; Immune cells; Metabolic checkpoints; Metabolic reprogramming; T cell; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-025-02407-6
  22. Front Cell Dev Biol. 2025 ;13 1653798
    Editorial: Microbiota homeostasis and metabolic reprogramming in cancer development and digestive diseases.
    Kai Li.
      
    Keywords:  cancer development; metabolic reprogramming; microbiota; therapeutic resistance; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2025.1653798
  23. Front Immunol. 2025 ;16 1627161
    Immunosuppressive cells in acute myeloid leukemia: mechanisms and therapeutic target.
    Mengnan Liu, Mengting Yang, Yue Qi, Yuting Ma, Qulian Guo, Ling Guo, Chunyan Liu, Wenjun Liu, Lan Xiao, You Yang.
      Immunotherapy has emerged as a cornerstone strategy for augmenting therapeutic efficacy in acute myeloid leukemia (AML). The immunosuppressive AML microenvironment, characterized by profound immune dysfunction, critically impairs anti-leukemic immune surveillance. This immunologically hostile niche is principally governed by specialized immunosuppressive cell populations-notably regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), leukemia-associated macrophages (LAMs), and regulatory B cells (Bregs)-which collectively establish an immune-privileged sanctuary for leukemic cells. This review critically examines three fundamental aspects of these immunosuppressive regulators in AML pathogenesis: (1) their recruitment dynamics within the leukemic niche, (2) the molecular mechanisms underlying their immunosuppressive functions, and (3) current and emerging therapeutic approaches designed to neutralize their inhibitory effects. Through this comprehensive analysis, we aim to provide a mechanistic framework for developing more effective immunotherapeutic interventions against AML.
    Keywords:  acute myeloid leukemia; leukemia-associated macrophages; leukemia-associated neutrophils; myeloid-derived suppressor cells; regulatory B cells; regulatory T cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1627161
  24. Crit Rev Oncol Hematol. 2025 Aug 05. pii: S1040-8428(25)00266-5. [Epub ahead of print] 104878
    Fatty acid in the tumor microenvironment: perspectives for immunotherapy.
    Ting Li, Yi-Ran Bie, Shan-Mei Chen, Yao Shang, Pei-Shan Hu.
      Fatty acids (FA) are essential macromolecules in living organisms and play critical roles in processes such as cancer development, inflammation, and autoimmunity. Immune responses and metabolic changes are involved in tumor occurrence, development, invasion, and metastasis, and therapies targeting immunity and metabolism have gradually begun to be developed in clinical practice. Recent studies have revealed alterations in fatty acid metabolism in tumor microenvironment, suggesting that the modulation of fatty acid metabolism can affect the efficacy of immunotherapy. In this review, we summarize the effects of fatty acids on cancer immunotherapy in aspects including tumor cell metabolism, protein lipid modification, and clinical applications. A deeper understanding of the mechanisms by which FA and their metabolites participate in immune response can enhance our knowledge of their function in tumor development and their impact on the immune system, thereby providing new strategies for improving cancer immunotherapy.
    Keywords:  Cancer immunotherapy; FAO; FAS; Fatty acid; Immune microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104878
  25. Front Immunol. 2025 ;16 1595124
    Recent progress in the study of exosomes in the gastric cancer immune microenvironment.
    Haibo Liu, Lei Zhu, Jianmei Yin.
      Gastric cancer (GC) ranks among the most prevalent forms of cancer and contributes significantly to cancer-related mortality. There exists a pressing need to investigate novel approaches for GC management to improve diagnostic methods, therapeutic interventions, and patient outcomes. Exosomes are nanoscale extracellular vesicles (EVs) derived from various cell types that carry a diverse range of biomolecular cargo, including DNA, RNA, proteins, lipids, and other bioactive constituents. They play significant roles in GC pathogenesis and tumor microenvironment (TME) modulation. Exosomes derived from cancer cells can enhance tumor progression, transform the TME, and modulate immune responses. Immune cell-derived exosomes can similarly modulate immune functions and the TME. Immunotherapy represents a GC treatment breakthrough and is expected to show efficacy when combined with exosome-targeted therapy. Abundant research has demonstrated that exosomes are crucial for tumor growth, immune evasion, immune microenvironment reconfiguration, and immunotherapy efficacy in GC. This review describes the role of exosomes in the GC microenvironment, focusing on the mechanisms by which exosomes regulate immune responses to GC, and summarizes the current status of and challenges in the development of exosome-based diagnostics and immunotherapy for GC.
    Keywords:  exosomes; gastric cancer; immunity; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1595124
  26. Front Immunol. 2025 ;16 1616514
    Alveolar macrophages maintain tissue localization and gain enhanced anti-tumor activity in Lewis lung carcinoma-reprogrammed lung microenvironment.
    Mengfei Ren, Jiaxiang Dou, Qian Yue, Liqin Ma, Hang Yu, Shengwen Shang, Shijie Wang, Jian Wang, Tingting Li, Fengqi Li.
      The role of alveolar macrophages (AMs) in lung carcinogenesis has been extensively studied, yielding significant insights. However, the status of AMs in tumor-bearing lungs remains incompletely characterized. Using orthotopic Lewis Lung Carcinoma (LLC) mouse models, we found that tumors induced an inflammatory extra-tumoral lung microenvironment (ETLME), distinct from the immunosuppressive tumor microenvironment (TME). T cells with an exhaustion phenotype and tumor-associated macrophages (TAMs) mainly accumulated in the TME rather than the ETLME. Surprisingly, AMs were absent from the tumor lesions and remained in the lung tissues, but they displayed a more active dynamic balance between proliferation and death in ETLME. Furthermore, AMs presented an activated phenotype characterized by upregulation of CD11b and downregulation of Siglec-F, elevated expression of inflammatory genes, and enhanced phagocytic and efferocytotic activity. Notably, AMs in ETLME retained their lipid metabolism capacity and responsiveness to external stimuli. More importantly, LLC-experienced AMs display enhanced anti-tumor ability. These findings indicate that AMs maintain their tissue localization and functional integrity within the ETLME.
    Keywords:  Lewis lung carcinoma; alveolar macrophages; extra-tumoral lung microenvironment; lung inflammation; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1616514
  27. Cancer Res. 2025 Aug 07.
    P2 Purinergic Receptors in Tumor Immunity.
    Xin Wang, Shu-Heng Jiang, Mingyue Ma, Shuqi Cai, Dong Song, Bing Han.
      P2 purinergic receptors are activated by extracellular adenosine triphosphate and other nucleotides released during cellular stress, hypoxia, or inflammation, serving as key mediators of intercellular communication. In cancer, they rapidly accumulate in the tumor microenvironment following cell death or metabolic stress. Activation of the P2 purinergic receptors P2X and P2Y can trigger both pro-inflammatory and immunosuppressive responses, and emerging evidence underscores P2 purinergic signaling as a central immunomodulator in cancer, critically shaping tumor immunobiology by coordinating immune cell interactions. This review explores how P2 purinergic signaling drives tumor progression through microenvironmental crosstalk and highlights therapeutic strategies targeting the pathway to disrupt pro-tumorigenic networks.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4624
  28. Front Biosci (Landmark Ed). 2025 Jun 30. 30(7): 27929
    Novel Insight into the Multiple Biological Characteristics of Polyamines in the Gut: From Structure to Function.
    Xinyi Yu, Shuzi Xin, Xiaohui Liu, Luming Pan, Weikai Shi, Yize Li, Hongli Wang, Xin Lu, Han Gao, Jingdong Xu.
      This review explores the structure of polyamines, including putrescine, spermidine, and spermine, and their crucial roles in immune cell functions. Polyamines are active compounds derived from ornithine that regulate signaling pathways by interacting with nucleic acids and proteins. Polyamines are essential for normal growth and development in immune cells, participating in cell signaling and neurotransmitter regulation and playing a critical role in immune responses. Notably, high concentrations of polyamines play a significant role in tumor cells and autoreactive B and T cells in autoimmune diseases. This impact should not be overlooked. Elevated levels of polyamines are associated with enhanced immune cell activity in tumor cells and autoimmune diseases. Furthermore, the connection between polyamines and normal immune cell functions, as well as their roles in autoimmune and antitumor immune cell functions, is significant. The role of polyamines in the normal function of activated T cells is well-established, and they are particularly important in antitumor immunity by modulating immune cell functions in the tumor microenvironment (TME). By synthesizing the latest research advancements, this review provides valuable insights into the roles of polyamines in immune regulation and outlines directions for future research.
    Keywords:  biological immunity; dysfunction; gut health; intestinal epithelium; polyamines
    DOI:  https://doi.org/10.31083/FBL27929
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