bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–03–09
twenty-six papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Immunometabolism of tumor-associated macrophages: A therapeutic perspective.
  2. The role of macrophages in liver metastasis: mechanisms and therapeutic prospects.
  3. B-Cell Co-culture in the Tumor Microenvironment of Solid Tumors Using Pancreatic Cancer as a Tumor Model.
  4. Metabolic crossroads: unravelling immune cell dynamics in gastrointestinal cancer drug resistance.
  5. The epigenetic hallmarks of immune cells in cancer.
  6. MicroRNA-induced reprogramming of tumor-associated macrophages for modulation of tumor immune microenvironment.
  7. The role of tenascin-C in tumor microenvironments and its potential as a therapeutic target.
  8. Immunoregulatory role of exosomal circRNAs in the tumor microenvironment.
  9. Interactions between the metabolic reprogramming of liver cancer and tumor microenvironment.
  10. Post-translational modifications in hepatocellular carcinoma: unlocking new frontiers in immunotherapy.
  11. How modulation of the tumor microenvironment drives cancer immune escape dynamics.
  12. Harnessing myeloid cells in cancer.
  13. [Drugs and cellular dynamics in tumor microenvironment using microphysiological systems].
  14. Cancer-associated fibroblasts in breast cancer in the single-cell era: Opportunities and challenges.
  15. Polyamine metabolism and anti-tumor immunity.
  16. LILRB4 specific overexpression in myeloid cells promotes tumor progression and immunosuppression in mouse models.
  17. The role of neutrophils and their immunosuppressive effects on prostate cancer.
  18. Clinical significance of the tumor microenvironment on immune tolerance in gastric cancer.
  19. Myeloid-derived suppressor cell-targeted virus-like particles synergistically activate innate immune response for cancer immunotherapy.
  20. MiRNA affects the advancement of breast cancer by modulating the immune system's response.
  21. Myeloid-derived suppressor cells in metabolic and cardiovascular disorders.
  22. Capsanthin inhibits migration and reduces N-linked glycosylation of PD-L1 via the EZH2-PD-L1 axis in triple-negative breast cancer brain metastasis.
  23. Cancer-associated fibroblasts serve as decoys to suppress NK cell anti-cancer cytotoxicity in breast cancer.
  24. Expanding the horizon of CAR T cell therapy: from cancer treatment to autoimmune diseases and beyond.
  25. Hepatic stellate cells functional heterogeneity in liver cancer.
  26. Metabolic engineering to facilitate anti-tumor immunity.
  1. Eur J Cancer. 2025 Feb 28. pii: S0959-8049(25)00113-3. [Epub ahead of print]220 115332
    Immunometabolism of tumor-associated macrophages: A therapeutic perspective.
    Adelya F Karimova, Adelya R Khalitova, Roman Suezov, Nikita Markov, Yana Mukhamedshina, Albert A Rizvanov, Magdalena Huber, Hans-Uwe Simon, Anna Brichkina.
      Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME), actively contributing to the formation of an immunosuppressive niche that fosters tumor progression. Consequently, there has been a growing interest in targeting TAMs as a promising avenue for cancer therapy. Recent advances in the field of immunometabolism have shed light on the influence of metabolic adaptations on macrophage physiology in the context of cancer. Here, we discuss the key metabolic pathways that shape the phenotypic diversity of macrophages. We place special emphasis on how metabolic reprogramming impacts the activation status of TAMs and their functions within the TME. Additionally, we explore alterations in TAM metabolism and their effects on phagocytosis, production of cytokines/chemokines and interaction with cytotoxic T and NK immune cells. Moreover, we examine the application of nanomedical approaches to target TAMs and assess the clinical significance of modulating the metabolism of TAMs as a strategy to develop new anti-cancer therapies. Taken together, in this comprehensive review article focusing on TAMs, we provide invaluable insights for the development of effective immunotherapeutic strategies and the enhancement of clinical outcomes for cancer patients.
    Keywords:  Immunometabolism; Nanomedicine; Tumor immunology; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.ejca.2025.115332
  2. Front Immunol. 2025 ;16 1542197
    The role of macrophages in liver metastasis: mechanisms and therapeutic prospects.
    Qin Yuan, Linlin Jia, Jiahua Yang, Wei Li.
      Metastasis is a hallmark of advanced cancer, and the liver is a common site for secondary metastasis of many tumor cells, including colorectal, pancreatic, gastric, and prostate cancers. Macrophages in the tumor microenvironment (TME) promote tumor cell metastasis through various mechanisms, including angiogenesis and immunosuppression, and play a unique role in the development of liver metastasis. Macrophages are affected by a variety of factors. Under conditions of hypoxia and increased acidity in the TME, more factors are now found to promote the polarization of macrophages to the M2 type, including exosomes and amino acids. M2-type macrophages promote tumor cell angiogenesis through a variety of mechanisms, including the secretion of factors such as VEGF, IL-1β, and TGF-β1. M2-type macrophages are subjected to multiple regulatory mechanisms. They also interact with various cells within the tumor microenvironment to co-regulate certain conditions, including the creation of an immunosuppressive microenvironment. This interaction promotes tumor cell metastasis, drug resistance, and immune escape. Based on the advent of single-cell sequencing technology, further insights into macrophage subpopulations in the tumor microenvironment may help in exploring new therapeutic targets in the future. In this paper, we will focus on how macrophages affect the TME, how tumor cells and macrophages as well as other immune cells interact with each other, and further investigate the mechanisms involved in liver metastasis of tumor cells and their potential as therapeutic targets.
    Keywords:  liver metastases; macrophages; therapy; traditional Chinese medicine; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1542197
  3. Methods Mol Biol. 2025 ;2909 225-244
    B-Cell Co-culture in the Tumor Microenvironment of Solid Tumors Using Pancreatic Cancer as a Tumor Model.
    Hend Abdelrasoul.
      B cells play a diverse role in the tumor microenvironment (TME) of solid tumors, influencing immune responses, tumor progression, and therapeutic outcomes. Depending on their activation state and interactions with other tumor components, they can exert both pro- and anti-tumor functions. They can promote tumor growth by secreting immunosuppressive cytokines or boost antitumor immunity by producing antitumor antibodies, presenting antigens, and activating T cells. Studying the effect of the TME on the phenotype and functionality of B cells is of great importance as their interactions with other TME components, such as cancer cells and stromal cells shape the immune landscape of the tumor. Gaining insight into these interactions sheds light on the mechanisms used by the tumor to evade immune detection. In this chapter, I summarize our current 3D co-culture system designed to investigate the effects of the TME on the functionality of B lymphocytes, using pancreatic ductal adenocarcinoma as a solid tumor model.
    Keywords:  3D co-culture system; B cells; Pancreatic ductal adenocarcinoma; Pancreatic stellate cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-1-0716-4442-3_15
  4. Cancer Drug Resist. 2025 ;8 7
    Metabolic crossroads: unravelling immune cell dynamics in gastrointestinal cancer drug resistance.
    Chahat Suri, Babita Pande, Lakkakula Suhasini Sahithi, Shashikant Swarnkar, Tuneer Khelkar, Henu Kumar Verma.
      Metabolic reprogramming within the tumor microenvironment (TME) plays a critical role in driving drug resistance in gastrointestinal cancers (GI), particularly through the pathways of fatty acid oxidation and glycolysis. Cancer cells often rewire their metabolism to sustain growth and reshape the TME, creating conditions such as nutrient depletion, hypoxia, and acidity that impair antitumor immune responses. Immune cells within the TME also undergo metabolic alterations, frequently adopting immunosuppressive phenotypes that promote tumor progression and reduce the efficacy of therapies. The competition for essential nutrients, particularly glucose, between cancer and immune cells compromises the antitumor functions of effector immune cells, such as T cells. Additionally, metabolic by-products like lactate and kynurenine further suppress immune activity and promote immunosuppressive populations, including regulatory T cells and M2 macrophages. Targeting metabolic pathways such as fatty acid oxidation and glycolysis presents new opportunities to overcome drug resistance and improve therapeutic outcomes in GI cancers. Modulating these key pathways has the potential to reinvigorate exhausted immune cells, shift immunosuppressive cells toward antitumor phenotypes, and enhance the effectiveness of immunotherapies and other treatments. Future strategies will require continued research into TME metabolism, the development of novel metabolic inhibitors, and clinical trials evaluating combination therapies. Identifying and validating metabolic biomarkers will also be crucial for patient stratification and treatment monitoring. Insights into metabolic reprogramming in GI cancers may have broader implications across multiple cancer types, offering new avenues for improving cancer treatment.
    Keywords:  Gastrointestinal cancers; drug resistance; immune cells; metabolic pathways; tumor microenvironment
    DOI:  https://doi.org/10.20517/cdr.2024.164
  5. Mol Cancer. 2025 Mar 05. 24(1): 66
    The epigenetic hallmarks of immune cells in cancer.
    Yu Ji, Chu Xiao, Tao Fan, Ziqin Deng, Di Wang, Wenpeng Cai, Jia Li, Tianle Liao, Chunxiang Li, Jie He.
      Targeting the dysregulation of epigenetic mechanisms in cancer has emerged as a promising therapeutic strategy. Although the significant rationale progress of epigenetic therapies in blocking cancer cells, how epigenetic regulation shapes tumor microenvironment (TME) and establishes antitumor immunity remains less understood. Recent study focus has been put on the epigenetic-mediated changes in the fate of immune cells, including the differentiation, expansion, recruitment, functionalization, and exhaustion of T cells, natural killer (NK) cells, tumor-associated macrophages (TAMs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and B cells within the TME. Here, we review the latest molecular and clinical insights into how DNA modifications, histone modification, and epitranscriptome-related regulations shape immune cells of various cancers. We also discuss opportunities for leveraging epigenetic therapies to improve cancer immunotherapies. This review provides the epigenetic foundations of cancer immunity and proposes the future direction of combination therapies.
    Keywords:  Cancer immunity; Epigenetics; Immune cells; Immunotherapy
    DOI:  https://doi.org/10.1186/s12943-025-02255-4
  6. J Control Release. 2025 Feb 28. pii: S0168-3659(25)00202-0. [Epub ahead of print] 113593
    MicroRNA-induced reprogramming of tumor-associated macrophages for modulation of tumor immune microenvironment.
    Yina Wu, Jinwon Park, Enzhen Xu, Dongyoon Kim, Jaiwoo Lee, Yu-Kyoung Oh.
      Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and typically exhibit pro-tumoral phenotypes. TAMs overexpress the signal regulatory protein alpha (SIRPα) receptor on their surface, which interacts with CD47 on tumor cells to inhibit their phagocytic activity. In this study, we developed lipid nanoparticles modified with an anti-SIRPα antibody (aSIRPα) for the targeted delivery of microRNA-155 (miR155@aSIRPα-LNP) to TAMs, aiming to enhance their anti-tumoral phenotypes within the tumor microenvironment. The aSIRPα modification not only facilitated nanoparticle uptake by TAMs rather than B16F10 cells, but also blocked the anti-phagocytosis signal by disrupting the interaction between SIRPα and CD47 on cancer cells. This dual functionality enhanced the expression of anti-tumoral phenotype markers in TAMs and activated macrophage-mediated phagocytosis of tumor cells. In a melanoma model, intratumoral administration of miR155@aSIRPα-LNP to B16F10 tumor-bearing mice reprogrammed TAMs toward anti-tumoral phenotypes. The anti-tumoral cytokines released by these TAMs remodeled the immunosuppressive tumor microenvironment, increasing cytotoxic T cell infiltration and reducing the regulatory T cell population, inhibiting tumor progression. This approach indicates the potential of miRNA-based therapies to overcome the limitations of current immunotherapies in treating cold solid tumors. Overall, the results suggest that delivering miR155 to TAMs by targeting SIRPα is a promising strategy for modulating the immunosuppressive tumor microenvironment in cancer immunotherapy.
    Keywords:  Lipid nanoparticle; MicroRNA; Reprogramming; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.jconrel.2025.113593
  7. Front Cell Dev Biol. 2025 ;13 1554312
    The role of tenascin-C in tumor microenvironments and its potential as a therapeutic target.
    Yaran Wang, Xiaohui Wen, Chao Su, Yanyi You, Ziqing Jiang, Qin Fan, Daoqi Zhu.
      The tumor microenvironment (TME) plays a pivotal role in cancer development and progression, and comprises various cellular and non-cellular components that interact with tumor cells. Tenascin-C (TNC) is an extracellular matrix glycoprotein that is widely expressed in the cancer stroma and influences critical processes, such as cell adhesion, migration, and immune modulation. This review examines the multifaceted roles of TNC in different TMEs, including the mechanical, immune, and metabolic microenvironments, as well as the radiation microenvironment (RME). In the context of the mechanical microenvironment, TNC actively participates in extracellular matrix remodeling, thereby facilitating tumor invasion. Notably, TNC exhibits immunosuppressive effects on T cells and promotes the recruitment of immunosuppressive cells within the immune microenvironment. Furthermore, TNC is implicated in the tumor hypoxia response, glucose metabolism reprogramming, and regulation of pH balance, underscoring its role in the metabolic microenvironment. Intriguingly, TNC also influences radiosensitivity within RME. This review also explores the potential of TNC as a biomarker for cancer prognosis and as a target for therapeutic interventions. By integrating recent advances in single-cell sequencing and spatial omics, we propose innovative strategies for leveraging TNC in personalized cancer therapy. Future research directions are discussed, focusing on distinct isoforms of TNC, their interaction networks, and their roles in radiotherapy efficacy. This comprehensive analysis underscores the importance of TNC in understanding tumor dynamics and improving cancer treatment outcomes.
    Keywords:  cancer biomarker; cancer therapeutics; immune modulation; radiation microenvironment; tenascin-c; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2025.1554312
  8. Front Oncol. 2025 ;15 1453786
    Immunoregulatory role of exosomal circRNAs in the tumor microenvironment.
    Cunming Lv, Jinhao Chen, Yuxiang Wang, Yichen Lin.
      As cancer incidence and mortality rates rise, there is an urgent need to develop effective immunotherapy strategies. Circular RNA (circRNA), a newly identified type of non-coding RNA, is abundant within cells and can be released via exosomes, facilitating communication between cells. Studies have demonstrated that exosomal circRNAs can alter the tumor microenvironment and modulate immune responses by influencing the functions of T cells, natural killer (NK) cells, and macrophages, thereby enabling tumors to evade the immune system. Moreover, exosomal circRNAs show potential as diagnostic biomarkers and therapeutic targets for cancer. This review summarizes the regulatory roles of exosomal circRNAs in immune cells and their potential applications in cancer progression and treatment, highlighting their promise in improving cancer immunotherapy. Future research should concentrate on understanding the mechanisms of key exosomal circRNAs and developing targeted immunotherapy methods.
    Keywords:  circular RNAs; exosomes; immunomodulation; signal pathway; tumor metastasis; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fonc.2025.1453786
  9. Front Immunol. 2025 ;16 1494788
    Interactions between the metabolic reprogramming of liver cancer and tumor microenvironment.
    Haoqiang Yang, Jinghui Li, Yiting Niu, Tao Zhou, Pengyu Zhang, Yang Liu, Yanjun Li.
      Metabolic reprogramming is one of the major biological features of malignant tumors, playing a crucial role in the initiation and progression of cancer. The tumor microenvironment consists of various non-cancer cells, such as hepatic stellate cells, cancer-associated fibroblasts (CAFs), immune cells, as well as extracellular matrix and soluble substances. In liver cancer, metabolic reprogramming not only affects its own growth and survival but also interacts with other non-cancer cells by influencing the expression and release of metabolites and cytokines (such as lactate, PGE2, arginine). This interaction leads to acidification of the microenvironment and restricts the uptake of nutrients by other non-cancer cells, resulting in metabolic competition and symbiosis. At the same time, metabolic reprogramming in neighboring cells during proliferation and differentiation processes also impacts tumor immunity. This article provides a comprehensive overview of the metabolic crosstalk between liver cancer cells and their tumor microenvironment, deepening our understanding of relevant findings and pathways. This contributes to further understanding the regulation of cancer development and immune evasion mechanisms while providing assistance in advancing personalized therapies targeting metabolic pathways for anti-cancer treatment.
    Keywords:  hepatocellular carcinoma; immune evasion; metabolism reprogram; signaling pathways; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1494788
  10. Front Immunol. 2025 ;16 1554372
    Post-translational modifications in hepatocellular carcinoma: unlocking new frontiers in immunotherapy.
    Yuexian Piao, Naicui Zhai, Xiaoling Zhang, Wenjie Zhao, Min Li.
      Liver cancer, particularly hepatocellular carcinoma (HCC), is one of the most common and aggressive malignancies worldwide. Immunotherapy has shown promising results in treating HCC, but its efficacy is often limited by complex mechanisms of immune evasion. Post-translational modifications (PTMs) of proteins play a critical role in regulating the immune responses within the tumor microenvironment (TME). These modifications influence protein function, stability, and interactions, which either promote or inhibit immune cell activity in cancer. In this mini-review, we explore the diverse PTMs that impact immune evasion in liver cancer, including glycosylation, phosphorylation, acetylation, and ubiquitination. We focus on how these PTMs regulate key immune checkpoint molecules such as PD-L1, CTLA-4, and the TCR complex. Furthermore, we discuss the potential of targeting PTMs in combination with existing immunotherapies to enhance the effectiveness of treatment in HCC. Understanding the role of PTMs in immune regulation may lead to the development of novel therapeutic strategies to overcome resistance to immunotherapy in liver cancer.
    Keywords:  glycosylation; hepatocellular carcinoma; immunotherapy; lactylation; post-translation modification
    DOI:  https://doi.org/10.3389/fimmu.2025.1554372
  11. Sci Rep. 2025 Mar 01. 15(1): 7308
    How modulation of the tumor microenvironment drives cancer immune escape dynamics.
    Pujan Shrestha, Zahra S Ghoreyshi, Jason T George.
      Metastatic disease is the leading cause of cancer-related death, despite recent advances in therapeutic interventions. Prior modeling approaches have accounted for the adaptive immune system's role in combating tumors, which has led to the development of stochastic models that explain cancer immunoediting and tumor-immune co-evolution. However, cancer immune-mediated dormancy, wherein the adaptive immune system maintains a micrometastatic population by keeping its growth in check, remains poorly understood. Immune-mediated dormancy can significantly delay the emergence (and therefore detection) of metastasis. An improved quantitative understanding of this process will thereby improve our ability to identify and treat cancer during the micrometastatic period. Here, we introduce a generalized stochastic model that incorporates the dynamic effects of immunomodulation within the tumor microenvironment on T cell-mediated cancer killing. This broad class of nonlinear birth-death model can account for a variety of cytotoxic T cell immunosuppressive effects, including regulatory T cells, cancer-associated fibroblasts, and myeloid-derived suppressor cells. We develop analytic expressions for the likelihood and mean time of immune escape. We also develop a method for identifying a corresponding diffusion approximation applicable to estimating population dynamics across a wide range of nonlinear birth-death processes. Lastly, we apply our model to estimate the nature and extent of immunomodulation that best explains the timing of disease recurrence in bladder and breast cancer patients. Our findings quantify the effects that stochastic tumor-immune interaction dynamics can play in the timing and likelihood of disease progression. Our analytical approximations provide a method of studying population escape in other ecological contexts involving nonlinear transition rates.
    Keywords:  Applied stochastic processes; Cancer immunotherapy; Diffusion approximation; Mathematical Oncology
    DOI:  https://doi.org/10.1038/s41598-025-91396-z
  12. Mol Cancer. 2025 Mar 06. 24(1): 69
    Harnessing myeloid cells in cancer.
    Su-Yeon Park, Ekaterina Pylaeva, Vikas Bhuria, Adriana Rosa Gambardella, Giovanna Schiavoni, Dimitrios Mougiakakos, Sung-Hoon Kim, Jadwiga Jablonska.
      Cancer-associated myeloid cells due to their plasticity play dual roles in both promoting and inhibiting tumor progression. Myeloid cells with immunosuppressive properties play a critical role in anti-cancer immune regulation. Cells of different origin, such as tumor associated macrophages (TAMs), tumor associated neutrophils (TANs), myeloid derived suppressor cells (also called MDSCs) and eosinophils are often expanded in cancer patients and significantly influence their survival, but also the outcome of anti-cancer therapies. For this reason, the variety of preclinical and clinical studies to modulate the activity of these cells have been conducted, however without successful outcome to date. In this review, pro-tumor activity of myeloid cells, myeloid cell-specific therapeutic targets, in vivo studies on myeloid cell re-polarization and the impact of myeloid cells on immunotherapies/genetic engineering are addressed. This paper also summarizes ongoing clinical trials and the concept of chimeric antigen receptor macrophage (CAR-M) therapies, and suggests future research perspectives, offering new opportunities in the development of novel clinical treatment strategies.
    Keywords:  Eosinophils; Immunosuppression; Macrophages; Myeloid cells; Neutrophils; Therapeutic target
    DOI:  https://doi.org/10.1186/s12943-025-02249-2
  13. Nihon Yakurigaku Zasshi. 2025 ;160(2): 97-101
    [Drugs and cellular dynamics in tumor microenvironment using microphysiological systems].
    Yuji Nashimoto.
      The tumor microenvironment (TME) includes immune cells, cancer-associated fibroblasts (CAFs), endothelial cells, pericytes, and more. Previously, these non-cancer cells were considered inactive components in cancer pathology. However, it has become evident that these cells and their secretions play crucial roles in cancer progression. To unravel the complexity of the TME and elucidate its mechanisms, microphysiological systems (MPS) have gained attention. An MPS is defined as "a microscale cell culture platform for in vitro modeling of functional features of a specific tissue or organ of human or animal origin", allowing for the control of the chemical or physical conditions of the TME and the analysis of the responses of cancer cells and surrounding cells. In recent years, the incorporation of vascular networks into tumor MPS has enabled more accurate assessments of the dynamics within the TME. This review provides an overview of the latest research on cancer MPS with vascular networks and the cellular and molecular dynamics within the TME.
    DOI:  https://doi.org/10.1254/fpj.24063
  14. Biochim Biophys Acta Rev Cancer. 2025 Feb 28. pii: S0304-419X(25)00033-2. [Epub ahead of print]1880(2): 189291
    Cancer-associated fibroblasts in breast cancer in the single-cell era: Opportunities and challenges.
    Jingtong Yang, Benkai Xin, Xiaoyu Wang, Youzhong Wan.
      Breast cancer is a leading cause of morbidity and mortality in women, and its progression is closely linked to the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), key components of the TME, play a crucial role in promoting tumor growth by driving cancer cell proliferation, invasion, extracellular matrix (ECM) remodeling, inflammation, chemoresistance, and immunosuppression. CAFs exhibit considerable heterogeneity and are classified into subgroups based on different combinations of biomarkers. Single-cell RNA sequencing (scRNA-seq) enables high-throughput and high-resolution analysis of individual cells. Relying on this technology, it is possible to cluster complex CAFs according to different biomarkers to analyze the specific phenotypes and functions of different subpopulations. This review explores CAF clusters in breast cancer and their associated biomarkers, highlighting their roles in disease progression and potential for targeted therapies.
    Keywords:  Breast cancer; Single-cell sequencing; Tumor microenvironment; cancer-associated fibroblasts
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189291
  15. Front Immunol. 2025 ;16 1529337
    Polyamine metabolism and anti-tumor immunity.
    Jing-Yi Wu, Yan Zeng, Yu-Yang You, Qi-Yue Chen.
      Growing attention has been directed toward the critical role of polyamines in the tumor microenvironment and immune regulation. Polyamines, primarily comprising putrescine, spermidine, and spermine, are tightly regulated through coordinated biosynthesis, catabolism, and transport, with distinct metabolic patterns between normal and cancerous tissues. Emerging evidence highlights the pivotal role of polyamine metabolism in tumor initiation, progression, and metastasis. This review aims to elucidate the differences in polyamine biosynthesis, transport, and catabolism between normal and cancerous tissues, as well as the associated alterations in tumor epigenetic modifications and resistance to immune checkpoint blockade driven by polyamine metabolism. Polyamine metabolism influences both tumor cells and the tumor microenvironment by modulating immune cell phenotypes-shifting them towards either tumor suppression or immune evasion within the tumor immune microenvironment. Additionally, polyamine metabolism impacts immunotherapy through its regulation of key enzymes. This review also explores potential therapeutic targets and summarizes the roles of polyamine inhibitors in combination with immunotherapy for cancer treatment, offering a novel perspective on therapeutic strategies.
    Keywords:  metabolism; polyamine; polyamine combination therapeutic strategies; tumor microenvironment; tumorigenesis
    DOI:  https://doi.org/10.3389/fimmu.2025.1529337
  16. Biochem Biophys Res Commun. 2025 Feb 25. pii: S0006-291X(25)00250-5. [Epub ahead of print]755 151536
    LILRB4 specific overexpression in myeloid cells promotes tumor progression and immunosuppression in mouse models.
    Hongying Wang, Shuhao Ji, Jiashen Zhang, Chunling Li, Xianhui Meng, Yuxiao Sun, Lei Wang, Huiwen Luan, Fangmin Li, Lijun Hui, Fang Li, Shuping Wei, Hong Yu, Zunling Li.
      Leukocyte immunoglobulin like receptor B4 (LILRB4) was considered to promote tumor progression and immunosuppression in various malignancies. As a murine homolog of LILRB4, gp49B has been employed in numerous mouse models to investigate the immunosuppressive properties of LILRB4. However, gp49B differs significantly from LILRB4 in its amino acid sequence and intracellular domains. In this study, we developed a conditional mouse model that overexpresses LILRB4 specifically in myeloid cells to investigate its effects on solid tumors and hematological malignancies. Our results showed that the physiological structure and overall immune system of LILRB4L/L; Cre mice were normal. LL2 tumors in LILRB4L/L; Cre mice exhibited increased size and weight, with elevated levels of immunosuppressive markers programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) on infiltrating CD3+ T cells, alongside a shift in tumor-associated macrophages (TAMs) from M1-type to M2-type. In the C1498 model, LILRB4 overexpression promoted tumor progression and metastasis, evidenced by increased bioluminescence and enhanced infiltration of monocytic myeloid-derived suppressor cells (M-MDSCs). Real-time PCR analysis showed upregulation of immunosuppressive mRNAs, including colony-stimulating factor 1 (CSF1), arginase1 (Arg1), macrophage galactose N-acetyl-galactosamine specific lectin 2 (Mgl2) and interleukin-1β (IL-1β) while downregulating pro-inflammatory markers like nitric oxide synthase 2 (Nos2). These findings indicate that LILRB4 fosters an immunosuppressive microenvironment that supports tumor progression. LILRB4L/L; Cre mice may serve as a promising tool for studying targeted LILRB4 tumor immunotherapy.
    Keywords:  Immunosuppression; LILRB4; Myeloid-derived suppressor cells; Tumor progression; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151536
  17. Histol Histopathol. 2025 Feb 20. 18890
    The role of neutrophils and their immunosuppressive effects on prostate cancer.
    Yihaoyun Lou, Zhiguo Fan, Shancheng Ren.
      Over the past decade, there has been a significant increase in the incidence of prostate cancer on a global scale, establishing it as the second most prevalent malignant tumor among European and American males. Neutrophils are myeloid immune cells that constitute a crucial proportion of inflammatory cells within the human circulatory system and actively contribute to the composition of the prostate tumor microenvironment (TME). Recent investigations have revealed that neutrophils are influenced by the surrounding tumor environment and possess a dual capacity to either promote or suppress cancer within the TME. Nevertheless, the precise mechanisms of neutrophils in prostate cancer remain inadequately elucidated. In this review, we aimed to comprehensively outline the character of neutrophils in the development and progression of prostate cancer while also exploring the clinical prognostic significance of the neutrophil-to-lymphocyte ratio (NLR).
    DOI:  https://doi.org/10.14670/HH-18-890
  18. Front Immunol. 2025 ;16 1532605
    Clinical significance of the tumor microenvironment on immune tolerance in gastric cancer.
    Xiangyang He, Xin-Yuan Guan, Yan Li.
      In the realm of oncology, the tumor microenvironment (TME)-comprising extracellular matrix components, immune cells, fibroblasts, and endothelial cells-plays a pivotal role in tumorigenesis, progression, and response to therapeutic interventions. Initially, the TME exhibits tumor-suppressive properties that can inhibit malignant transformation. However, as the tumor progresses, various factors induce immune tolerance, resulting in TME behaving in a state that promotes tumor growth and metastasis in later stages. This state of immunosuppression is crucial as it enables TME to change from a role of killing tumor cells to a role of promoting tumor progression. Gastric cancer is a common malignant tumor of the gastrointestinal tract with an alarmingly high mortality rate. While chemotherapy has historically been the cornerstone of treatment, its efficacy in prolonging survival remains limited. The emergence of immunotherapy has opened new therapeutic pathways, yet the challenge of immune tolerance driven by the gastric cancer microenvironment complicates these efforts. This review aims to elucidate the intricate role of the TME in mediating immune tolerance in gastric cancer and to spotlight innovative strategies and clinical trials designed to enhance the efficacy of immunotherapeutic approaches. By providing a comprehensive theoretical framework, this review seeks to advance the understanding and application of immunotherapy in the treatment of gastric cancer, ultimately contributing to improved patient outcomes.
    Keywords:  gastric cancer; immunosuppression; immunotherapy; metabolize; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1532605
  19. J Control Release. 2025 Mar 04. pii: S0168-3659(25)00212-3. [Epub ahead of print] 113603
    Myeloid-derived suppressor cell-targeted virus-like particles synergistically activate innate immune response for cancer immunotherapy.
    Zhixiong Zhu, Shuqin Cao, Hanwen Li, Zongliang Zhang, Qizhong Lu, Hexian Li, Luxuan Shen, Zeng Wang, Nian Yang, Jiayun Yu, Jianshu Li, Meijun Zheng, Chunlai Nie, Aiping Tong, Bin Shao.
      The importance of the tumor microenvironment in dynamically modulating neoplastic process, fostering proliferation, survival and migration is now widely appreciated. Therapeutics directed to various components of tumor microenvironment, especially tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs), have become an attractive avenue for cancer immunotherapy. Virus-like particles (VLPs) derived from cowpea chlorotic mottle viruses (CCMV) have been used extensively in biotechnology and are ideal platforms for the targeted delivery of therapeutic drugs for cancer immunotherapy. Here, oxidative dsDNAs, which have excellent immunostimulatory effects, are encapsulated into CCMV (CPD VLPs). CPD VLPs could be effectively taken up by macrophages and subsequently trigger Cyclic GMP-AMP synthase-stimulator of interferon genes pathway and NLRP3/Caspase-1/Gasdermin D -dependent pyroptosis pathway. To increase tumor-targeting specificity and reduce toxicity in bystander healthy tissues, peptides targeting MDSCs are conjugated to the exterior surfaces of the CPD VLPs named CPD-TP VLPs. CPD-TP VLPs can home to tumor side and induce a robust antitumor response by reprogramming tumor microenvironment. Notably, CPD-TP VLPs administration is also efficacious against lung metastasis from breast cancer. Moreover, the combination of CPD-TP VLPs with programmed cell death protein 1 (PD-1) blockade could improve therapeutic response of PD-1 antibody treatment in "immune-cold" mouse tumor models. Therefore, this study presents a novel design for VLP-based cancer vaccine.
    Keywords:  Immunotherapy; Tumor microenvironment; Virus-like particles; cancer vaccine
    DOI:  https://doi.org/10.1016/j.jconrel.2025.113603
  20. Biochim Biophys Acta Mol Basis Dis. 2025 Mar 03. pii: S0925-4439(25)00104-8. [Epub ahead of print]1871(5): 167759
    MiRNA affects the advancement of breast cancer by modulating the immune system's response.
    Yeqin Fu, Qiuhui Yang, Ning Xu, Xiping Zhang.
      Breast cancer (BC), which is the most common tumor in women, has greatly endangered women's lives and health. Currently, patients with BC receive comprehensive treatments, including surgery, chemotherapy, radiotherapy, endocrine therapy, and targeted therapy. According to the latest research, the development of BC is closely related to the inflammatory immune response, and the immunogenicity of BC has steadily been recognized. As such, immunotherapy is one of the promising and anticipated forms of treatment for BC. The potential values of miRNA in the diagnosis and prognosis of BC have been established, and aberrant expression of associated miRNA can either facilitate or inhibit progression of BC. In the tumor immune microenvironment (TME), miRNAs are considered to be an essential molecular mechanism by which tumor cells interact with immunocytes and immunologic factors. Aberrant expression of miRNAs results in reprogramming of tumor cells actively, which may suppress the generation and activation of immunocytes and immunologic factors, avoid tumor cells apoptosis, and ultimately result in uncontrolled proliferation and deterioration. Therefore, through activating and regulating the immunocytes related to tumors and associated immunologic factors, miRNA can contribute to the advancement of BC. In this review, we assessed the function of miRNA and associated immune system components in regulating the advancement of BC, as well as the potential and viability of using miRNA in immunotherapy for BC.
    Keywords:  Breast cancer; Immune checkpoint; Immune system; Interleukins (ILs); Tumor Infiltrating Lymphocytes (TILs); Tumor Necrosis Factor-α (TNF-α); Tumor-Associated Macrophages (TAMs); miRNA
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167759
  21. Trends Endocrinol Metab. 2025 Mar 01. pii: S1043-2760(25)00024-4. [Epub ahead of print]
    Myeloid-derived suppressor cells in metabolic and cardiovascular disorders.
    Jingwei Yan, Shuai Guo, Jun He, Hanpeng Huang, Yiming Xu.
      Dysregulation of immune homeostasis can precipitate chronic inflammation, thus significantly contributing to the onset and progression of metabolic and cardiovascular diseases. Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population of immature myeloid cells that are mobilized in response to biological stressors such as tissue damage and inflammation. Although MDSCs have been extensively characterized in the contexts of cancer and infectious diseases, emerging evidence highlights their pivotal roles in the pathophysiology of metabolic and cardiovascular disorders. We discuss growing evidence for the involvement of MDSCs in the progression of metabolic and cardiovascular diseases, with the aim of deepening our understanding of MDSCs in cardiometabolic physiology and identifying the necessary steps for the development of innovative MDSC-targeted therapeutic strategies.
    Keywords:  cardiovascular disorders; metabolic disorders; myeloid-derived suppressor cell
    DOI:  https://doi.org/10.1016/j.tem.2025.02.001
  22. Cell Death Discov. 2025 Mar 04. 11(1): 85
    Capsanthin inhibits migration and reduces N-linked glycosylation of PD-L1 via the EZH2-PD-L1 axis in triple-negative breast cancer brain metastasis.
    Yi-Chung Chien, Jia-Yan Wu, Liang-Chih Liu, Yung-Luen Yu.
      Breast cancer metastasis to the brain, occurring in about 15-25% of cases, represents a major obstacle in the treatment of triple-negative breast cancer (TNBC). The molecular mechanisms driving this form of metastasis are still largely unknown. PD-L1, an immune checkpoint protein, is central to tumor immune evasion and has become a focus for immunotherapy development. While PD-L1 inhibitors have shown success in various cancer types, their effectiveness in TNBC brain metastases remains to be fully investigated. This highlights the urgent need to understand the complex interactions between metastatic brain tumors and the tumor microenvironment in TNBC patients. Gaining insights into these dynamics is crucial for developing new targeted therapies, including those that modulate the PD-L1 pathway, to better manage and treat TNBC brain metastases. We explore the impact of Capsanthin on the tumor microenvironment of brain metastases in triple-negative breast cancer (TNBC). Our results reveal that Capsanthin effectively inhibits the migration of brain metastasis TNBC cells. Furthermore, Capsanthin significantly reduces the expression of EZH2 and N-linked glycosylated PD-L1 proteins and mRNA in TNBC cells, encompassing both primary and metastatic sites, as well as in mesenchymal stem cells (3A6). Data from The Cancer Genome Atlas (TCGA) indicate that elevated expression levels of EZH2 correlate with poorer patient prognosis. Immunoprecipitation assays demonstrate a direct interaction between EZH2 and PD-L1 in brain metastases of TNBC, underscoring the pivotal role of the EZH2-PD-L1 axis. Additionally, Capsanthin was found to suppress the expression of epithelial-mesenchymal transition (EMT) markers in metastatic brain TNBC cells and mesenchymal stem cells. Our results suggest that Capsanthin can modulate the tumor microenvironment and inhibit key pathways involved in cancer progression, offering potential therapeutic benefits for patients with TNBC brain metastases.
    DOI:  https://doi.org/10.1038/s41420-025-02368-1
  23. Cancer Discov. 2025 Mar 10.
    Cancer-associated fibroblasts serve as decoys to suppress NK cell anti-cancer cytotoxicity in breast cancer.
    Aviad Ben-Shmuel, Yael Gruper, Coral Halperin, Oshrat Levi-Galibov, Hallel Rosenberg-Fogler, Debra Barki, Giulia Carradori, Yaniv Stein, Gal Yagel, Mariia Naumova, Shimrit Mayer, Maya Dadiani, Dana Morzaev-Sulzbach, Ofra Golani, Reinat Nevo, Ziv Porat, Einav Nili Gal-Yam, Ruth Scherz-Shouval.
      Cancer-associated fibroblasts (CAFs) are abundant components of the breast tumor microenvironment and major contributors to immune-modulation. CAFs regulate the activity of many immune cells including T-cells, macrophages and dendritic cells, however little is known about their interaction with natural killer (NK) cells, which constitute an important arm of anti-tumor immunity. Using mouse models of breast cancer and ex-vivo co-cultures, we find that CAFs inhibit NK cell cytotoxicity towards cancer cells. We unravel the mechanism by which suppression occurs, through ligand-receptor engagement between NK cells and CAFs, leading to CAF cytolysis and downregulation of activating receptor expression on NK cells, promoting cancer cell escape from NK cell surveillance. In triple negative breast cancer patients, we find enrichment of NK cells in CAF-rich regions, and upregulation of NK binding ligands on CAFs which correlates with poor disease outcome. These results reveal a CAF-mediated immunosuppressive decoy mechanism with implications for treatment of carcinomas.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0131
  24. Front Immunol. 2025 ;16 1544532
    Expanding the horizon of CAR T cell therapy: from cancer treatment to autoimmune diseases and beyond.
    Zishan Yang, Bingjun Ha, Qinhan Wu, Feng Ren, Zhinan Yin, Hongru Zhang.
      Chimeric antigen receptor (CAR)-T-cell therapy has garnered significant attention for its transformative impact on the treatment of hematologic malignancies such as leukemia and lymphoma. Despite its remarkable success, challenges such as resistance, limited efficacy in solid tumors, and adverse side effects remain prominent. This review consolidates recent advancements in CAR-T-cell therapy and explores innovative engineering techniques and strategies to overcome the immunosuppressive tumor microenvironment (TME). We also discuss emerging applications beyond cancer, including autoimmune diseases and chronic infections. Future perspectives highlight the development of more potent CAR-T cells with increased specificity and persistence and reduced toxicity, providing a roadmap for next-generation immunotherapies.
    Keywords:  CAR-T cells; adoptive immunotherapy; autoimmune diseases; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1544532
  25. Semin Liver Dis. 2025 Mar 05.
    Hepatic stellate cells functional heterogeneity in liver cancer.
    Laura Sererols-Viñas, Gemma Garcia-Vicién, Paloma Ruiz-Blázquez, Tingfang Lee, Youngmin Lee, Ester Gonzalez-Sanchez, Javier Vaquero, Anna Moles, Aveline Filliol, Silvia Affò.
      Hepatic stellate cells (HSCs) are the liver's pericytes, and play key roles in liver homeostasis, regeneration, fibrosis and cancer. Upon injury, HSCs activate and are the main origin of myofibroblasts and cancer associated fibroblasts (CAFs) in liver fibrosis and cancer. Primary liver cancer has a grim prognosis, ranking as the 3rd leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) being the predominant type, followed by intrahepatic cholangiocarcinoma (iCCA). Moreover, the liver hosts 35% of all metastatic lesions. The distinct spatial distribution and functional roles of HSCs across these malignancies represent a significant challenge for universal therapeutic strategies, requiring a nuanced and tailored understanding of their contributions. This review examines the heterogeneous roles of HSCs in liver cancer, focusing on their spatial localization, dynamic interactions within the tumor microenvironment (TME), and emerging therapeutic opportunities, including strategies to modulate their activity, and harness their potential as targets for anti-fibrotic and anti-tumor interventions.
    DOI:  https://doi.org/10.1055/a-2551-0724
  26. Cancer Cell. 2025 Feb 21. pii: S1535-6108(25)00056-X. [Epub ahead of print]
    Metabolic engineering to facilitate anti-tumor immunity.
    Tanya Schild, Patrick Wallisch, Yixuan Zhao, Ya-Ting Wang, Lyric Haughton, Rachel Chirayil, Kaitlyn Pierpont, Kevin Chen, Sara Nunes-Violante, Justin Cross, Elisa de Stanchina, Craig B Thompson, David A Scheinberg, Justin S A Perry, Kayvan R Keshari.
      Fructose consumption is elevated in western diets, but its impact on anti-tumor immunity is unclear. Fructose is metabolized in the liver and small intestine, where fructose transporters are highly expressed. Most tumors are unable to drive glycolytic flux using fructose, enriching fructose in the tumor microenvironment (TME). Excess fructose in the TME may be utilized by immune cells to enhance effector functions if engineered to express the fructose-specific transporter GLUT5. Here, we show that GLUT5-expressing CD8+ T cells, macrophages, and chimeric antigen receptor (CAR) T cells all demonstrate improved effector functions in glucose-limited conditions in vitro. GLUT5-expressing T cells show high fructolytic activity in vitro and higher anti-tumor efficacy in murine syngeneic and human xenograft models in vivo, especially following fructose supplementation. Together, our data demonstrates that metabolic engineering through GLUT5 enables immune cells to efficiently utilize fructose and boosts anti-tumor immunity in the glucose-limited TME.
    Keywords:  CAR-T; fructose; macrophages; metabolic engineering; slc2a5; t cell
    DOI:  https://doi.org/10.1016/j.ccell.2025.02.004
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