bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–05–18
twenty-two papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Immunometabolism of Innate Immune Cells in Gastrointestinal Cancer.
  2. Tumor Microenvironment: A Complex Landscape of Cancer Development and Drug Resistance.
  3. Metabolic reprogramming in hepatocellular carcinoma: mechanisms of immune evasion and therapeutic implications.
  4. Crosstalk between the tumor immune microenvironment and metabolic reprogramming in pancreatic cancer: new frontiers in immunotherapy.
  5. Role of FHOD1 in tumor cells and tumor immune microenvironment.
  6. Role of cancer cell-derived exosomal glycoproteins in macrophage polarization.
  7. Mechanisms of tumor-associated macrophages promoting tumor immune escape.
  8. A Systematic Review of Immune Cell Roles in Breast Cancer Immunotherapy.
  9. The potential application of stroma modulation in targeting tumor cells: focus on pancreatic cancer and breast cancer models.
  10. Non-canonical extracellular complement pathways and the complosome paradigm in cancer: a scoping review.
  11. Immune cell-derived exosomal non-coding RNAs in tumor microenvironment: Biological functions and potential clinical applications.
  12. Immune Checkpoint Inhibitors and Immunosuppressive Tumor Microenvironment: Current Challenges and Strategies to Overcome Resistance.
  13. Cancer-associated fibroblasts (CAFs) and plaque-associated fibroblasts (PAFs): Unraveling the cellular crossroads of atherosclerosis and cancer.
  14. CSF1-CAR Specifically Targets CSF1R+ Pancreatic Cancer Cells and Tumor-Associated Macrophages.
  15. Emerging therapeutics targeting tumor-associated macrophages for the treatment of solid organ cancers.
  16. Progress of exosomes in regulating tumor metastasis by remodeling the pre-metastatic immune microenvironment.
  17. Histone modifications and metabolic reprogramming in tumor-associated macrophages: a potential target of tumor immunotherapy.
  18. Regulatory T Cells in Tumor Microenvironment: Therapeutic Approaches and Clinical Implications.
  19. ER stress and/or ER-phagy in drug resistance? Three coincidences are proof.
  20. Radiotherapy-induced alterations in tumor microenvironment: metabolism and immunity.
  21. Role of tumor microenvironment in ovarian cancer metastasis and clinical advancements.
  22. Targeting GPX4 palmitoylation to boost antitumor immunity.
  1. Cancers (Basel). 2025 Apr 27. pii: 1467. [Epub ahead of print]17(9):
    Immunometabolism of Innate Immune Cells in Gastrointestinal Cancer.
    Izabela Siemińska, Marzena Lenart.
      Cancer cells are often described as voracious consumers of nutrients, with glucose frequently cited as a key energy source; however, their metabolic plasticity allows them to adapt and utilize various substrates, including lipids and amino acids, to sustain growth and survival. However, the metabolic demands of immune cells within the tumor microenvironment (TME) are less commonly discussed despite their critical role in shaping the immune response. In this review, we explored the intricate interplay between immunometabolism and innate immunity cells in gastrointestinal cancers. We focused on how metabolic pathways, including glycolysis, fatty acid oxidation, and amino acid metabolism, drive the immunosuppressive functions of myeloid-derived suppressor cells (MDSCs) and tumor-associated neutrophils (TANs), tumor-associated macrophages (TAMs) and innate lymphocyte subsets such as NK cells. These cells contribute to a hostile immune landscape, supporting tumor growth and evasion from immune surveillance in a phenomenon of tumor-derived immunosuppression. Additionally, we investigated the influence of dietary interventions on the metabolic reprogramming of these immune cells, highlighting how nutrition can modulate the TME. Finally, we discussed emerging therapeutic strategies that target metabolic vulnerabilities in MDSCs, TANs, NK cells, and monocytes, offering a novel avenue for enhancing antitumor immunity. By dissecting these mechanisms, we aim to provide insights into how metabolic pathways can be harnessed to improve cancer treatment outcomes. This review underscores the importance of understanding immunometabolism not only as a driver of immune suppression but also as a potential therapeutic target in gastrointestinal cancer.
    Keywords:  colorectal cancer; gastrointestinal cancer; immunometabolism; innate immune cells
    DOI:  https://doi.org/10.3390/cancers17091467
  2. Cureus. 2025 Apr;17(4): e82090
    Tumor Microenvironment: A Complex Landscape of Cancer Development and Drug Resistance.
    Sohaila Fatima.
      Cancer is responsible for nearly one in six global fatalities, making it a major health issue worldwide. Despite advancements in early detection, surgery, and targeted therapies, effective treatment remains challenging due to the complexity and heterogeneity of the disease. A key factor in cancer progression and resistance to treatment is the tumor microenvironment (TME). It is a complex ecosystem comprising cancer cells, stromal cells, immune cells, extracellular matrix (ECM), and soluble factors like cytokines and chemokines. These components interact dynamically to influence tumor growth, metastasis, immune evasion, and treatment resistance. Cancer cells drive the formation of the TME by releasing signaling molecules, while stromal cells, such as fibroblasts and endothelial cells, support tumor metabolism, angiogenesis, and invasion. Immune cells within the TME can either suppress or promote tumor progression, depending on their activation state. Additionally, the TME can promote the growth of immunosuppressive cells that aid cancer cells in evading immune surveillance, such as regulatory T-cells and myeloid-derived suppressor cells. The TME also impedes drug delivery by creating defective blood vessels, contributing to drug resistance. Recent technological advancements have deepened our understanding of the TME, revealing its role in immune modulation, metabolism, and extracellular matrix remodeling. As a result, targeting the TME has become a promising strategy to overcome treatment resistance and improve cancer therapy outcomes.
    Keywords:  cancer development; drug resistance; immunotherapy; targeted medicines; tumor microenvironment
    DOI:  https://doi.org/10.7759/cureus.82090
  3. Front Immunol. 2025 ;16 1592837
    Metabolic reprogramming in hepatocellular carcinoma: mechanisms of immune evasion and therapeutic implications.
    Bocheng Gao, Yan Lu, Xingyue Lai, Xi Xu, Shuhua Gou, Zhida Yang, Yanju Gong, Hong Yang.
      Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with limited treatment options for advanced stages. Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to the harsh tumor microenvironment (TME) and evade immune surveillance. This review involves the role of metabolic reprogramming in HCC, focusing on the dysregulation of glucose, lipid, and amino acid metabolism, and its impact on immune evasion. Key metabolic pathways, such as the Warburg effect, fatty acid synthesis, and glutaminolysis, are discussed, along with their influence on tumor-associated macrophages (TAMs) and immune cell function. Targeting these metabolic alterations presents a promising therapeutic approach to enhance immunotherapy efficacy and improve HCC patient outcomes.
    Keywords:  TME; hepatocellular carcinoma; immune evasion; immunotherapy; metabolic reprogramming; tumor microenvironment; tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3389/fimmu.2025.1592837
  4. Front Immunol. 2025 ;16 1564603
    Crosstalk between the tumor immune microenvironment and metabolic reprogramming in pancreatic cancer: new frontiers in immunotherapy.
    Jintai Shi, Xiaoyan Cui, Junlin Wang, Guangqia Liu, Jiayin Meng, Yingjie Zhang.
      In recent years, the incidence and mortality of pancreatic cancer (PC) are increasing year by year. The highly heterogeneous nature of PC, its strong immune escape ability and easy metastasis make it the most lethal malignant tumor in the world. With the rapid development of sequencing technology, the complex components in the tumor microenvironment (TME) of PC have been gradually revealed. Interactions between pancreatic stellate cells, tumor-associated fibroblasts, various types of immune cells, and cancer cells collectively promote metabolic reprogramming of all types of cells. This metabolic reprogramming further enhances the immune escape mechanism of tumor cells and ultimately induces tumor cells to become severely resistant to chemotherapy and immunotherapy. On the one hand, PC cells achieve re and rational utilization of glucose, amino acids and lipids through metabolic reprogramming, which in turn accomplishes biosynthesis and energy metabolism requirements. Under such conditions, tumorigenesis, proliferation and metastasis are ultimately promoted. On the other hand, various types of immune cells in the tumor immune microenvironment (TIME) also undergo metabolic reprogramming, which leads to tumor progression and suppression of anti-immune responses by inhibiting the function of normal anti-tumor immune cells and enhancing the function of immunosuppressive cells. The aim of this review is to explore the interaction between the immune microenvironment and metabolic reprogramming in PC. The focus is to summarize the specific mechanisms of action of metabolic reprogramming of PC cells and metabolic reprogramming of immune cells. In addition, this review will summarize the mechanisms of immunotherapy resistance in PC cells. In the future, targeting specific mechanisms of metabolic reprogramming will provide a solid theoretical basis for the development of combination therapies for PC.
    Keywords:  PC; immunotherapy; mechanisms; metabolic reprogramming; time
    DOI:  https://doi.org/10.3389/fimmu.2025.1564603
  5. Front Immunol. 2025 ;16 1514488
    Role of FHOD1 in tumor cells and tumor immune microenvironment.
    Yang Yang, Zhanting Kang, Jinlong Cai, Shan Jia, Shangqian Fan, Huifang Zhu.
      FHOD 1 (Formin homology 2 domain containing protein 1) is a member of Diaphanous-related formins (DRFs) which contains a GTP-binding domain (GBD), formin homology (FH) 1 and FH 2 domains, a coiled-coil, and a diaphanous-like autoregulatory domain. Studies have shown that FHOD1 can not only regulate intracellular signals in tumor cells but also regulate various components of the tumor microenvironment (TME), such as T cells, B cells, cancer-associated fibroblasts (CAFs), some cytokines. Aberrant expression and dysfunction of the FHOD1 protein play a key role in tumor immunosuppression. Specifically, FHOD1 can impair function of chemokine receptors that are supposed to direct immune cells to localize to the tumor site accurately. As a result of this impairment, immune cells cannot migrate efficiently into TME, thereby impairing their ability to attack tumor cells. In addition, FHOD1 activated signaling pathways within the immune cells abnormally, resulting in their inability to recognize and destroy tumor cells effectively. Therefore, FHOD1 ultimately leads to a state of immunosuppression in TME, providing favorable conditions for the growth and spread of tumor cells. Altogether this review provides an in-depth understanding of the role of FHOD1 in tumor immunosuppression.
    Keywords:  FHOD1; PD-1; PDL1; epithelial-mesenchymal transition; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1514488
  6. Mol Biol Rep. 2025 May 10. 52(1): 451
    Role of cancer cell-derived exosomal glycoproteins in macrophage polarization.
    Khandu Wadhonkar, Yashi Singh, Aurelia Rughetti, Soumalya Das, Rigzin Yangdol, M Hassan Sk, Mirza S Baig.
      Cancer is a deadly disease marked by abnormal cell growth, proliferation, and metastasis-the spread of cancer from its origin to distant sites. A key factor in tumor progression is the tumor microenvironment (TME), which significantly influences tumor behavior and response to treatment. Within the TME, interactions between cancer cells and surrounding immune cells, particularly tumor-associated macrophages (TAMs), play a critical role in shaping immune responses. This review focuses on recent findings from a systematic PubMed search regarding cancer cell-derived exosomal glycoproteins and their role in modulating macrophage phenotypes. Tumor-derived exosomes, a type of extracellular vesicle (EV), carry glycoproteins-proteins with attached sugar chains-that can influence macrophage polarization. These glycoproteins can reprogram macrophages into either the M1 phenotype (proinflammatory and anti-tumor) or the M2 phenotype (anti-inflammatory and tumor-supportive). The M1 macrophages inhibit tumor progression, while M2 macrophages support tumor growth by promoting immune suppression and tissue remodeling. Understanding how exosomal glycoproteins drive this polarization offers critical insight into cancer immunology and may pave the way for novel therapeutic strategies targeting the TME.
    Keywords:  Cancer; Exosomes; Glycoproteins; Immunomodulation; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s11033-025-10535-x
  7. Carcinogenesis. 2025 May 15. pii: bgaf023. [Epub ahead of print]
    Mechanisms of tumor-associated macrophages promoting tumor immune escape.
    Shengfen Li, Mengxia Zhang, Yuan Gao, Can Zhao, Shuxian Liao, Xuhong Zhao, Qian Ning, Shengsong Tang.
      The phenomenon of tumor immune escape involves multiple mechanisms that enable tumor cells to evade recognition and assault by the host's immune system, facilitating their survival and growth within the organism. Furthermore, tumor immune escape represents a critical mechanism in tumor progression and significantly contributes to the unsuccessful outcomes of immunotherapy. Tumor-associated macrophages (TAMs) are recruited into the tumor microenvironment (TME), serving a pivotal role in modulating tumor immune escape. An increasing body of research has demonstrated that TAMs are linked to unfavorable cancer prognosis and drug resistance. They suppress immune cell activity, hinder antigen presentation, and inhibit T cell activation, thereby helping tumor cells evade immune attacks. Consequently, elucidating the mechanisms by which TAMs promote tumor immune escape is crucial for developing novel immunotherapeutic strategies and improving the efficacy of cancer immunotherapy. In terms of clinical relevance, studies on TAMs have revealed their significant roles in various types of cancer. In recent years, transformational therapies such as CSF-1R inhibitors and CD40 agonists targeting TAMs have entered clinical trials and are expected to reverse immunosuppression and enhance immunotherapy response. These studies provide new directions for improving the effectiveness of existing immunotherapies and overcoming drug resistance.
    Keywords:  checkpoint inhibition; cytokine; immune escape; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1093/carcin/bgaf023
  8. Cancer Rep (Hoboken). 2025 May;8(5): e70217
    A Systematic Review of Immune Cell Roles in Breast Cancer Immunotherapy.
    Rui Li, Wei Lv, Dong Liang Wang, Na Chen.
       BACKGROUND: Breast cancer (BC) is the most prevalent malignancy among women and is associated with high mortality and significant clinical challenges. Although conventional treatments such as surgery, chemotherapy, and radiotherapy have significantly improved patient survival, their efficacy remains limited by severe side effects and treatment resistance. In recent years, advances in immunotherapy have underscored the pivotal role of immune cells in treating BC.
    RECENT FINDINGS: This systematic review summarizes the current knowledge on the roles of immune cells within the BC tumor microenvironment (TME), including their phenotypes, functions, and implications for immunotherapy. Following PRISMA guidelines, 71 studies published between 2010 and 2024 were analyzed. The results indicate that immune cell populations-such as tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), natural killer (NK) cells, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs)-are integral to tumor progression and therapeutic response. However, their functional heterogeneity and plasticity remain key obstacles to the development of effective and personalized immunotherapeutic strategies.
    CONCLUSION: Further research is needed to clarify the mechanisms governing immune cell behavior within the BC TME and to advance precision immunotherapy. Such insights will lay the foundation for individualized treatment approaches, ultimately improving patient outcomes and quality of life (QoL).
    Keywords:  breast cancer; immune cells; immunotherapy; tumor microenvironment; vaccines
    DOI:  https://doi.org/10.1002/cnr2.70217
  9. Semin Cancer Biol. 2025 May 13. pii: S1044-579X(25)00060-4. [Epub ahead of print]
    The potential application of stroma modulation in targeting tumor cells: focus on pancreatic cancer and breast cancer models.
    Giuseppina Roscigno, Sacha Jacobs, Belen Toledo, Roberto Borea, Gianluca Russo, Francesco Pepe, Maria Jose Serrano, Viola Calabrò, Giancarlo Troncone, Roberto Giovannoni, Elisa Giovannetti, Umberto Malapelle.
      The tumor microenvironment (TME) plays a crucial role in cancer development and spreading being considered as "the dark side of the tumor". Within this term tumor cells, immune components, supporting cells, extracellular matrix and a myriad of bioactive molecules that synergistically promote tumor development and therapeutic resistance, are included. Recent findings revealed the profound impacts of TME on cancer development, serving as physical support, critical mediator and biodynamic matrix in cancer evolution, immune modulation, and treatment outcomes. TME targeting strategies built on vasculature, immune checkpoints, and immuno-cell therapies, have paved the way for revolutionary clinical interventions. On this basis, the relevance of pre-clinical and clinical investigations has rapidly become fundamental for implementing novel therapeutical strategies breaking cell-cell and cell -mediators' interactions between TME components and tumor cells. This review summarizes the key players in the breast and pancreatic TME, elucidating the intricate interactions among cancer cells and their essential role for cancer progression and therapeutic resistance. Different tumors such breast and pancreatic cancer have both different and similar stroma features, that might affect therapeutic strategies. Therefore, this review aims to comprehensively evaluate recent findings for refining breast and pancreatic cancer therapies and improve patient prognoses by exploiting the TME's complexity in the next future.
    Keywords:  breast cancer; new targeting agents; pancreatic cancer; stroma; tumour microenvironment
    DOI:  https://doi.org/10.1016/j.semcancer.2025.05.003
  10. Front Immunol. 2025 ;16 1519465
    Non-canonical extracellular complement pathways and the complosome paradigm in cancer: a scoping review.
    Camila de Freitas Oliveira-Tore, Amarilis Giaretta de Moraes, Helena Musetti B S Plácido, Nathalia M D L Signorini, Pamela Dias Fontana, Tatiane da Piedade Batista Godoy, Angelica Beate Winter Boldt, Iara de Messias.
      The Complement System (CS) comprises three catalytic pathways that can be activated by specific immune triggers. However, within the tumor microenvironment (TME), CS intracellular components, recently named as complosome, play roles that extend beyond the activation and regulation of its pathways. The interaction between TME elements and tumor cells alters the local immune response, leading to inflammation, cell proliferation, and tumor invasion. Our focus is on understanding the significance of complosome and non-canonical pathways in cancer. In this scoping review, we analyzed 45 articles that discussed the various roles of CS components in carcinogenesis. Many CS components, including C1q, C3a-C3aR, C5a-C5aR, factor H, and properdin, some of them at the intracellular level, may play a dual role in tumor progression, demonstrating either anti-tumor or pro-tumor activity independent of complement pathway activation. The specific function of each component can influence both the type and stage of tumor cells. There is a notable lack of studies on the role of the lectin pathway in tumor development, and this knowledge gap must be addressed to fully understand the role of complosome in cancer. Nevertheless, the activation of CS and the roles of its components in complosome pathways are crucial steps in tumor development.
    Keywords:  C1q; C3; C5; cancer; complement system; non-canonical activation pathway
    DOI:  https://doi.org/10.3389/fimmu.2025.1519465
  11. Chin J Cancer Res. 2025 Apr 30. 37(2): 250-267
    Immune cell-derived exosomal non-coding RNAs in tumor microenvironment: Biological functions and potential clinical applications.
    Chenguang Liu, Yawen Luo, Huan Zhou, Meixi Lin, Dan Zang, Jun Chen.
      The intricate interactions between immune cells and tumors exert a profound influence on cancer progression and therapeutic efficacy. Within the tumor microenvironment, exosomes have emerged as pivotal mediators of intercellular communication, with their cargo of non-coding RNAs (ncRNAs) serving as key regulatory elements. This review examines the multifaceted roles of immune cell-derived exosomal ncRNAs in tumor biology. The involvement of various immune cells, including T cells, B cells, natural killer cells, macrophages, neutrophils, and myeloid-derived suppressor cells, in utilizing exosomal ncRNAs to regulate tumor initiation and progression is explored. Additionally, the biogenesis and delivery mechanisms of these immune cell-derived exosomal ncRNAs are discussed, alongside their potential clinical applications in cancer.
    Keywords:  Tumor; clinical applications; exosome; immune; non-coding RNAs
    DOI:  https://doi.org/10.21147/j.issn.1000-9604.2025.02.10
  12. Immunopharmacol Immunotoxicol. 2025 May 16. 1-45
    Immune Checkpoint Inhibitors and Immunosuppressive Tumor Microenvironment: Current Challenges and Strategies to Overcome Resistance.
    Gurpreet Singh Gill, Simmi Kharb, Gitanjali Goyal, Prasenjit Das, Kailash Chand Kurdia, Ruby Dhar, Subhradip Karmakar.
      Immune checkpoint inhibitors (ICIs) are shown to improve cancer treatment effectiveness by boosting the immune system of the patient. Nevertheless, the unique and highly suppressive TME poses a significant challenge, causing heterogeneity of response or resistance in a considerable number of patients. This review focuses on the evasive attributes of the TME. Immune evasion mechanism in TME include immunosuppressive cells, cytokine and chemokine signaling, metabolic alterations and overexpression of immune checkpoint molecules such as PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA and their interactions within the TME. In addition, this review focuses on the overcoming resistance by targeting immunosuppressive cells, normalizing tumor blood vessels, blocking two or three checkpoints simultaneously, combining vaccines, oncolytic viruses and metabolic inhibitors with ICIs or other therapies. This review also focuses on the necessity of finding predictive markers for the stratification of patients and to check response of ICIs treatment. It remains to be made certain by new research and intelligent innovations how these discoveries of the TME and its interplay facilitate ICI treatment and change the face of cancer treatment.
    Keywords:  ICIs Resistance; Immune Checkpoint Inhibitors (ICIs); Immunosuppression; Tumor Microenvironment (TME)
    DOI:  https://doi.org/10.1080/08923973.2025.2504906
  13. Biomed Pharmacother. 2025 May 14. pii: S0753-3322(25)00339-7. [Epub ahead of print]188 118145
    Cancer-associated fibroblasts (CAFs) and plaque-associated fibroblasts (PAFs): Unraveling the cellular crossroads of atherosclerosis and cancer.
    Gavino Faa, Pina Ziranu, Andrea Pretta, Flaviana Cau, Massimo Castagnola, Dario Spanu, Giorgio Saba, Alessandra Pia D'Agata, Ekta Tiwari, Jasjit S Suri, Mario Scartozzi, Luca Saba.
      Atherosclerosis is a complex process involving various cells and molecules within the atherosclerotic plaque. Recent evidence suggests that plaque-associated fibroblasts (PAFs), also known as atherosclerosis-associated fibroblasts (AAFs), might play a significant role in the development and progression of the disease. The microenvironment of the atherosclerotic plaque, resembling the tumor microenvironment (TME), includes various cellular populations like plaque-associated macrophages (PAMs), plaque-associated neutrophils (PANs), vascular smooth muscle cells (VSMCs), myeloid-derived suppressor cells (MDSCs), and PAFs. Similar to cancer-associated fibroblasts (CAFs) in tumors, PAFs exhibits a wide range of characteristics and functions. Their interactions with endothelial cells, smooth muscle cells, and other stromal cells, including adventitial fibroblast precursors, significantly influence atherosclerosis progression. Moreover, the ability of PAFs to express various markers such as alpha-SMA, Desmin, VEGF, and GFAP, highlights their diverse origins from different precursor cells, including vascular smooth muscle cells, endothelial cells, glial cells of the enteric nervous system, adventitial fibroblast precursors, as well as resident and circulating fibrocytes. This article explores the molecular interactions between PAFs, cells associated with atherosclerosis, and other stromal cells. It further examines the role of PAFs in the development and progression of atherosclerosis, and compares their features with those of CAFs. The research suggests that studying tumor-associated fibroblasts can help understand fibroblast subpopulations in atherosclerotic plaque. Identifying specific subpopulations could provide new insight into atherosclerosis complexity and lead to the development of innovative drugs for medical intervention.
    Keywords:  Atherosclerosis; Cancer; Cancer-associated fibroblasts; Fibroblasts; Plaque-associated fibroblasts
    DOI:  https://doi.org/10.1016/j.biopha.2025.118145
  14. J Immunother. 2025 May 16.
    CSF1-CAR Specifically Targets CSF1R+ Pancreatic Cancer Cells and Tumor-Associated Macrophages.
    Yongjie Zhu, Ruipu Sun, Jiawei Fan, Haiyan Ma, Bin Sun.
       SUMMARY: A highly suppressive tumor immune microenvironment and nonspecific target endow malignant tumors with CAR-T cells. CSF1R is highly expressed on pancreatic cancer tissues compares with normal tissues in GEPIA database and M2 macrophages mainly contributing to the suppressive tumor microenvironment (TME), suggesting that CSF1R is a suitable antigen. CSF1 is the natural ligand of CSF1R, so we constructed a CSF1-CAR and tested its cytotoxic effect on tumor cells and macrophages in vitro. Our results demonstrated that CSF1-CAR-T cells can lyse tumor cells dependent on CSF1R expression. Meanwhile, CSF1-CAR-T also lyse CSF1R+ M2 macrophages, suggesting that CSF1-CAR-T cells play a role in eliminating tumor cells and remodeling the TME.
    Keywords:  CAR-T; CSF1; CSF1R; tumor-associated macrophage
    DOI:  https://doi.org/10.1097/CJI.0000000000000563
  15. Expert Opin Emerg Drugs. 2025 May 12.
    Emerging therapeutics targeting tumor-associated macrophages for the treatment of solid organ cancers.
    Dandan Li, Udo Rudloff.
       INTRODUCTION: Over the last decade, immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 or CTLA-4 which reinvigorate T cells for tumor control have become standard-of-care treatment options. In response to the increasingly recognized mechanisms of resistance to T cell activation in immunologically cold tumors, immuno-oncology drug development has started to shift beyond T cell approaches. These include tumor-associated macrophages (TAMs), a major pro-tumor immune cell population in the tumor microenvironment known to silence immune responses.
    AREAS COVERED: Here we outline anti-TAM therapies in current development, either as monotherapy or in combination with other treatment modalities. We describe emerging drugs targeting TAMs under investigation in phase II and III testing with a focus on their distinguishing mechanism of action which include (1) reprogramming of TAMs toward anti-tumor function and immune surveillance, (2) blockade of recruitment, and (3) reduction and ablation of TAMs.
    EXPERT OPINION: Several new immuno-oncology agents are under investigation to harness anti-tumor functions of TAMs. While robust anti-tumor efficacy of anti-TAM therapies across advanced solid organ cancers remains elusive to-date, TAM reprogramming therapies have yielded benefits in select cancers. The inherent heterogeneity of the diverse TAM population will require enhanced investments into biomarker-driven approaches to fully leverage its therapeutic potential.
    Keywords:  CD40 agonists; Macrophages; STING agonists; TAM-depleting therapeutics; TAM-reprogramming therapeutics; Toll-like receptor (TLR) agonists; Tumor-associated macrophages (TAMs); anti-TAM therapy; chemokine & chemokine receptor antagonists; phagocytosis checkpoint inhibitors
    DOI:  https://doi.org/10.1080/14728214.2025.2504376
  16. Cell Immunol. 2025 May 09. pii: S0008-8749(25)00045-0. [Epub ahead of print]413 104960
    Progress of exosomes in regulating tumor metastasis by remodeling the pre-metastatic immune microenvironment.
    Jiangning Xiang, Lin Yao, Shan Wang, Lei Zhao, Jing Yu.
      Exosomes play an important role in the metastatic microenvironment, acting as a transmission belt that facilitates intercellular communication. By delivering proteins, nucleic acids, and other substances in the exosomes, they can change the function of the receptor target cells, change the microenvironment of the metastatic site, and promote the colonization of the tumor cells, thus promoting cancer metastasis. The interaction between tumor cells and the surrounding microenvironment is complex, with exosomes serving as key facilitators of crosstalk between the primary tumor microenvironment and the pre-metastasis microenvironment. Despite many current studies to explore exosomes, we still do not have a detailed understanding of the role and mechanism of exosomes in the pre-metastatic immune microenvironment, and there are many challenges in the clinical application of exosomes. In this paper, we summarize the role of exosomes in regulating the pre-metastatic immune microenvironment and its mechanism, focusing on how exosomes regulate the function of immune cells in the pre-metastatic microenvironment to promote tumor metastasis. In addition, the potential application of exosomes in tumor immunotherapy and strategies for targeting exosomes are discussed. This will contribute to the immunotherapy of cancer metastasis and promote the clinical application of exosomes.
    Keywords:  Exosome; Immune cell; Immune microenvironment; Pre-metastatic microenvironment; cancer metastasis
    DOI:  https://doi.org/10.1016/j.cellimm.2025.104960
  17. Front Immunol. 2025 ;16 1521550
    Histone modifications and metabolic reprogramming in tumor-associated macrophages: a potential target of tumor immunotherapy.
    Yiting Xu, Han Zhang, Dengyun Nie.
      Histone modifications, including methylation, acetylation, lactylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation, and crotonylation, critically regulate tumor-associated macrophages (TAMs) polarization by modulating gene expression and functional states. Reprogramming TAMs from M2 to M1 phenotypes through epigenetic targeting has emerged as a promising strategy to enhance anti-tumor immunity and improve the efficacy of cancer immunotherapy. This review explores the role of histone modifications in TAM biology, their interplay with metabolic reprogramming, and the opportunities and challenges in developing epigenetic-based therapies to advance cancer immunotherapy.
    Keywords:  epigenetics; histone modifications; immunotherapy; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1521550
  18. Cell Biol Int. 2025 May 14.
    Regulatory T Cells in Tumor Microenvironment: Therapeutic Approaches and Clinical Implications.
    Niti Sureka, Sufian Zaheer.
      Regulatory T cells (Tregs), previously referred to as suppressor T cells, represent a distinct subset of CD4+ T cells that are uniquely specialized for immune suppression. They are characterized by the constitutive expression of the transcription factor FoxP3 in their nuclei, along with CD25 (the IL-2 receptor α-chain) and CTLA-4 on their cell surface. Tregs not only restrict natural killer cell-mediated cytotoxicity but also inhibit the proliferation of CD4+ and CD8+ T-cells and suppress interferon-γ secretion by immune cells, ultimately impairing an effective antitumor immune response. Treg cells are widely recognized as a significant barrier to the effectiveness of tumor immunotherapy in clinical settings. Extensive research has consistently shown that Treg cells play a pivotal role in facilitating tumor initiation and progression. Conversely, the depletion of Treg cells has been linked to a marked delay in tumor growth and development.
    Keywords:  FOXP3; Tregs; regulatory T cells; tumor microenvironment
    DOI:  https://doi.org/10.1002/cbin.70031
  19. Cell Commun Signal. 2025 May 13. 23(1): 223
    ER stress and/or ER-phagy in drug resistance? Three coincidences are proof.
    Sameer Kumar Panda, Ibone Rubio Sanchez-Pajares, Ayesha Rehman, Vitale Del Vecchio, Luigi Mele, Sandhya Chipurupalli, Nirmal Robinson, Vincenzo Desiderio.
      Cancer is influenced by the tumor microenvironment (TME), which includes factors such as pH, hypoxia, immune cells, and blood vessels. These factors affect cancer cell growth and behavior. The tumor microenvironment triggers adaptive responses such as endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and autophagy, posing a challenge to cancer treatment. The UPR aims to restore ER homeostasis by involving key regulators inositol-requiring enzyme-1(IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Additionally, ER-phagy, a selective form of autophagy, eliminates ER components under stress conditions. Understanding the interplay between hypoxia, ER stress, UPR, and autophagy in the tumor microenvironment is crucial for developing effective cancer therapies to overcome drug resistance. Targeting the components of the UPR and modulating ER-phagy could potentially improve the efficacy of existing cancer therapies. Future research should define the conditions under which ER stress responses and ER-phagy act as pro-survival versus pro-death mechanisms and develop precise methods to quantify ER-phagic flux in tumor cells.
    Keywords:  Autophagy; Drug resistance; ER Stress; ER-phagy; UPR
    DOI:  https://doi.org/10.1186/s12964-025-02232-w
  20. Front Cell Dev Biol. 2025 ;13 1568634
    Radiotherapy-induced alterations in tumor microenvironment: metabolism and immunity.
    Jinpeng Chen, Sheng Wang, Yue Ding, Duo Xu, Shiya Zheng.
      Tumor metabolism plays a pivotal role in shaping immune responses within the tumor microenvironment influencing tumor progression, immune evasion, and the efficacy of cancer therapies. Radiotherapy has been shown to impact both tumor metabolism and immune modulation, often inducing immune activation through damage-associated molecular patterns and the STING pathway. In this study, we analyse the particular characteristics of the tumour metabolic microenvironment and its effect on the immune microenvironment. We also review the changes in the metabolic and immune microenvironment that are induced by radiotherapy, with a focus on metabolic sensitisation to the effects of radiotherapy. Our aim is to contribute to the development of research ideas in the field of radiotherapy metabolic-immunological studies.
    Keywords:  immune modulation; metabolic reprogramming; radiotherapy; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2025.1568634
  21. J Transl Med. 2025 May 14. 23(1): 539
    Role of tumor microenvironment in ovarian cancer metastasis and clinical advancements.
    Yang Wang, Na Zhu, Jing Liu, Fang Chen, Yang Song, Yue Ma, Zhuo Yang, Danbo Wang.
      Ovarian cancer (OC) is the most lethal gynecological malignancy worldwide, characterized by heterogeneity at the molecular, cellular and anatomical levels. Most patients are diagnosed at an advanced stage, characterized by widespread peritoneal metastasis. Despite optimal cytoreductive surgery and platinum-based chemotherapy, peritoneal spread and recurrence of OC are common, resulting in poor prognoses. The overall survival of patients with OC has not substantially improved over the past few decades, highlighting the urgent necessity of new treatment options. Unlike the classical lymphatic and hematogenous metastasis observed in other malignancies, OC primarily metastasizes through widespread peritoneal seeding. Tumor cells (the "seeds") exhibit specific affinities for certain organ microenvironments (the "soil"), and metastatic foci can only form when there is compatibility between the "seeds" and "soil." Recent studies have highlighted the tumor microenvironment (TME) as a critical factor influencing the interactions between the "seeds" and "soil," with ascites and the local peritoneal microenvironment playing pivotal roles in the initiation and progression of OC. Prior to metastasis, the interplay among tumor cells, immunosuppressive cells, and stromal cells leads to the formation of an immunosuppressive pre-metastatic niche in specific sites. This includes characteristic alterations in tumor cells, recruitment and functional anomalies of immune cells, and dysregulation of stromal cell distribution and function. TME-mediated crosstalk between cancer and stromal cells drives tumor progression, therapy resistance, and metastasis. In this review, we summarize the current knowledge on the onset and metastatic progression of OC. We provide a comprehensive discussion of the characteristics and functions of TME related to OC metastasis, as well as its association with peritoneal spread. We also outline ongoing relevant clinical trials, aiming to offer new insights for identifying potential effective biomarkers and therapeutic targets in future clinical practice.
    Keywords:  Growth; Immune cells; Metastasis; Ovarian cancer; Stromal cells; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-025-06508-0
  22. Trends Cancer. 2025 May 14. pii: S2405-8033(25)00121-9. [Epub ahead of print]
    Targeting GPX4 palmitoylation to boost antitumor immunity.
    Daehee Hwang, Whitney S Henry.
      Despite significant milestones in cancer immunotherapy, tumor cells often escape immune surveillance. Zhou et al. revealed that the pivotal ferroptosis suppressor glutathione peroxidase 4 (GPX4) can undergo palmitoylation by zDHHC8, enhancing ferroptosis resistance. This study highlights the potential of targeting GPX4 palmitoylation to enhance cytotoxic T cell-mediated ferroptosis of tumor cells.
    Keywords:  GPX4; ferroptosis; immune-checkpoint blockade (ICB); palmitoylation; tumor microenvironment (TME); zDHHC8
    DOI:  https://doi.org/10.1016/j.trecan.2025.05.001
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