bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–06–08
28 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. The impact of the tumor microenvironment on macrophages.
  2. Mechanical forces and immune cells in the tumor microenvironment: from regulation mechanism to therapeutic strategies.
  3. Myeloid-Derived Suppressor Cells in Cancer: Mechanistic Insights and Targeted Therapeutic Innovations.
  4. Immunometabolism of regulatory T cells in cancer.
  5. Interplay between cancer-associated fibroblasts and dendritic cells: implications for tumor immunity.
  6. The plasticity of cancer-associated fibroblasts.
  7. Dissecting the dual role of OTU family proteins in tumor progression and immune escape.
  8. CAFs Defang NK Cells to Promote Breast Cancer Immunosuppression.
  9. Targeting myeloid cells in pancreatic ductal adenocarcinoma: from primary tumors to liver metastasis.
  10. Crosstalk between metabolic reprogramming and microbiota: implications for cancer progression and novel therapeutic opportunities.
  11. Reprogrammed immuno-metabolic environment of cancer: the driving force of ferroptosis resistance.
  12. Emerging immunotherapy and tumor microenvironment for advanced sarcoma: a comprehensive review.
  13. Unraveling the role of M2 TAMs in ovarian cancer dynamics: a systematic review.
  14. Tumor-associated macrophages (TAMs): Constructing an immunosuppressive microenvironment bridge for pancreatic ductal adenocarcinoma (PDAC).
  15. The impact of cancer therapy on the cells and extracellular vesicles of the tumor immune microenvironment.
  16. Research progress of galectins in glioma.
  17. Combination strategies of gut microbiota in cancer therapy through metabolic reprogramming and immune remodeling.
  18. A new approach to the treatment of ovarian cancer: The application of CAR-T cell therapy.
  19. Unraveling the advances of non-coding RNAs on the tumor microenvironment: innovative strategies for cancer therapies.
  20. Interleukin-enhanced CAR-engineered immune cells in tumor immunotherapy: current insights and future perspectives.
  21. Melanoma innervation, noradrenaline and cancer progression in zebrafish xenograft model.
  22. Editorial: Vital role of innate immunity in cancer immunotherapy.
  23. Targeting Regnase-1 unleashes CAR T cell antitumor activity for osteosarcoma and creates a proinflammatory tumor microenvironment.
  24. Tumor-infiltrating lymphocytes in cancer immunotherapy: from chemotactic recruitment to translational modeling.
  25. Chronic compression drives macrophages toward a pathological pro-tumor state.
  26. Organoids technology in cancer research: from basic applications to advanced ex vivo models.
  27. Pan-cancer analysis reveals multifaceted roles of nonmyelinating Schwann cells in gastrointestinal cancers.
  28. Recent advances in regulatory immune cells: exploring the world beyond Tregs.
  1. Front Immunol. 2025 ;16 1572764
    The impact of the tumor microenvironment on macrophages.
    Man Xiao, Xiaoduan Li.
      The tumor microenvironment (TME), which has crucial roles in tumor progression, metastasis, and drug resistance, contains abundant immune cells. The most influential of these include tumor-associated macrophages (TAMs), which both secrete microenvironment-modifying cytokines and are acted upon by various other components of the microenvironment. The heterogeneity and diversity of TAMs are closely associated with patients' response to tumor immunotherapy; thus, therapeutic targeting of TAMs has become a research focus in recent years. Although numerous studies have explored how TAMs alter the microenvironment, relatively few have investigated the impact of the microenvironment on TAMs. In this review, we discuss the effects of various components of the tumor microenvironment on TAMs from the perspectives of recruitment, reprogramming, and functional modulation, with a focus on the cellular components of the microenvironment. We also summarize the development of immunotherapies targeting TAMs, which have shown promising results in clinical trials.
    Keywords:  functional modulation; macrophages; recruitment; reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1572764
  2. Int J Surg. 2025 Jun 05.
    Mechanical forces and immune cells in the tumor microenvironment: from regulation mechanism to therapeutic strategies.
    Tonghui Ren, Lingqi Sun, Yichen Zheng, Yixuan Jiang, Yan Guo, Ji Ma.
      The tumor microenvironment (TME) plays a crucial regulatory role in the initiation and progression of tumors. Mechanical forces in the TME, such as matrix stiffness, solid stress, fluid shear force, and microstructural changes, can regulate the activity, migration, and proliferation of immune cells through mechanical transduction pathways, thereby affecting the growth and immune evasion of tumor cells. However, the precise mechanisms by which mechanical forces regulate immune cells and their impact on immunotherapy are not yet fully understood. This review aims to explore how mechanical forces in the TME regulate T cells, natural killer (NK) cells, tumor-associated macrophages (TAMs), B cells, neutrophils, and dendritic cells (DCs), and influence immunotherapy. Additionally, this review emphasizes the temporal effects of mechanical forces on immune cells during tumor progression, and highlights the need to investigate the interactions of different mechanical forces in the TME and their combined effects on immune cells. These insights can provide a theoretical basis and research directions for optimizing future tumor treatment strategies based on mechanical regulation.
    Keywords:  immune cells; mechanical forces; mechanical regulation; therapeutic strategies; tumor microenvironment
    DOI:  https://doi.org/10.1097/JS9.0000000000002636
  3. MedComm (2020). 2025 Jun;6(6): e70231
    Myeloid-Derived Suppressor Cells in Cancer: Mechanistic Insights and Targeted Therapeutic Innovations.
    Tianying Hu, Jianxue Zhai, Zhanda Yang, Jiajia Peng, Chuxuan Wang, Xinyao Liu, Yawen Li, Jiaqi Yao, Fengxi Chen, Haixia Li, Taixue An, Zongcai Liu, Haifang Wang.
      Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that expand aberrantly in cancer and exhibit potent immunosuppressive properties. They contribute to tumor progression through both immunological and nonimmunological mechanisms. Immunologically, MDSCs suppress antitumor responses by inhibiting effector cells such as T cells and NK cells, facilitating immune evasion. Nonimmunologically, they promote tumor growth and metastasis through processes such as the epithelial‒mesenchymal transition, angiogenesis, and premetastatic niche formation. MDSC accumulation is closely linked to accelerated tumor progression, including resistance to both immunotherapies and conventional treatments, making these cells critical therapeutic targets. Clinical studies have demonstrated the potential of MDSC-targeted strategies to improve treatment efficacy. However, challenges remain in achieving specificity and effectiveness in MDSC-targeted therapies, emphasizing the need for a deeper understanding of their biology. This review summarizes the origin, classification, and biological characteristics of MDSCs, their dual roles in tumor progression, and their clinical significance. We also discuss recent advances in clinical and preclinical studies, including both traditional targeted therapies and emerging innovative strategies. By integrating current findings, we aim to provide a comprehensive perspective on the role of MDSCs in cancer and valuable insights for advancing cancer treatment and drug development.
    Keywords:  MDSC phenotype; biomarker potential; myeloid‐derived suppressor cells (MDSCs); therapeutic strategy; tumor microenvironment (TME); tumor‐promoting mechanisms
    DOI:  https://doi.org/10.1002/mco2.70231
  4. Oncogene. 2025 Jun 04.
    Immunometabolism of regulatory T cells in cancer.
    Jordy Saravia, Hongbo Chi.
      Regulatory T (Treg) cells play critical roles in maintaining immune tolerance and tissue homeostasis, but impede anti-tumor immunity. Recent work has established how Treg cells metabolically adapt within the tumor microenvironment (TME), and these adaptations frequently provide a functional advantage over effector T cells. Further, enhanced Treg cell function in the TME may contribute to the limited efficacy of current immunotherapies, especially immune checkpoint blockade (ICB). Here, we review recent progress in understanding mechanisms of Treg cell heterogeneity and function in tumors, with a particular focus on cellular metabolism as an underlying factor by which Treg cells are uniquely poised to thrive in the TME and contribute to tumorigenesis. We describe how cellular metabolism and nutrient or metabolic communication shape Treg cell lineage identity and function in the TME. We also discuss the interplay between ICB and Treg cell metabolism and function, and highlight current strategies targeting Treg cell metabolism specifically in the TME. Understanding metabolic control of intratumoral Treg cells provides excellent opportunities to uncover new or combination therapies for cancer.
    DOI:  https://doi.org/10.1038/s41388-025-03458-1
  5. Front Immunol. 2025 ;16 1515390
    Interplay between cancer-associated fibroblasts and dendritic cells: implications for tumor immunity.
    Fátima María Mentucci, María Gracia Ferrara, Agustina Ercole, Natalia Belén Rumie Vittar, María Julia Lamberti.
      The tumor microenvironment (TME) plays a critical role in cancer progression, with cancer-associated fibroblasts (CAFs) emerging as key players in immune evasion. This review explores the complex interactions between CAFs and dendritic cells (DCs), essential antigen-presenting cells that activate immune responses. CAFs impair DC maturation and function by secreting cytokines, chemokines, and growth factors, reducing their ability to present antigens and stimulate T cells, thus promoting an immunosuppressive environment favorable to tumor growth. Additionally, CAFs contribute to the differentiation of tolerogenic DCs, fostering regulatory T cells (Tregs) that further suppress antitumor immunity. This review examines the molecular mechanisms underlying CAF-DC crosstalk and discusses potential therapeutic strategies aimed at restoring DC functionality. Targeting the CAF-driven immunosuppressive network offers promising opportunities to enhance the efficacy of DC-based vaccines and immunotherapies, paving the way for improved cancer treatment outcomes.
    Keywords:  cancer; immunosuppression; immunotherapy; oncoimmunology; stroma; tolerogenicity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1515390
  6. Trends Cancer. 2025 Jun 04. pii: S2405-8033(25)00108-6. [Epub ahead of print]
    The plasticity of cancer-associated fibroblasts.
    Zihan Xia, Olivier De Wever.
      The plasticity of cancer-associated fibroblasts (CAFs) refers to their ability to adopt a spectrum of distinct phenotypes or states in response to dynamic changes within the tumor microenvironment (TME). Recent advances in single-cell technologies have enabled detailed characterization of the heterogeneity and spatial complexity of CAF subpopulations across multiple tumor types. Notably, CAF subtypes undergo dynamic transitions during tumor progression and therapy pressure. This review systematically summarizes the current knowledge on CAF plasticity shaped by both intrinsic and extrinsic factors, delineates research gaps, and highlights CAF phenotypic switching as a potential therapeutic opportunity.
    Keywords:  cancer-associated fibroblasts; fibroblast heterogeneity; fibroblast plasticity; phenotype switching; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2025.04.012
  7. Front Immunol. 2025 ;16 1544341
    Dissecting the dual role of OTU family proteins in tumor progression and immune escape.
    Xiaolong Tang, Yadan Li, Yongshuo Liu.
      As a core mechanism regulating intracellular protein homeostasis, the dynamic equilibrium between ubiquitination and deubiquitination profoundly impacts the functionality and fate of target proteins. The Ovarian tumor domain (OTU) family, a vital subclass of deubiquitinating enzymes, comprises 16 members that mediate ubiquitin binding and hydrolysis through their characteristic OTU domain. Recent years have witnessed growing interest in OTU family members in oncology and immunology research. This review comprehensively elucidates the core mechanisms by which OTU members regulate tumor-associated signaling networks via substrate-specific deubiquitination. On one hand, they directly govern tumor cell proliferation, metastasis, and apoptosis by modulating the stability of key substrates. On the other hand, they orchestrate tumor progression through dynamic regulation of inflammatory intensity, immune response duration, and immune evasion mechanisms within the tumor microenvironment (TME), thereby constructing a multidimensional regulatory network in tumor development. These findings not only unveil the pivotal role of OTU family members in tumorigenesis and immune modulation but also establish a theoretical foundation for developing novel anti-tumor therapeutics targeting deubiquitination processes. Notably, OTUs emerge as high-potential therapeutic targets with high translational relevance for refining precision-guided tumor-immunotherapy integration strategies.
    Keywords:  OTU family; deubiquitinating enzymes; immune regulation; tumorigenesis; ubiquitination-deubiquitination balance
    DOI:  https://doi.org/10.3389/fimmu.2025.1544341
  8. Cancer Discov. 2025 Jun 03. 15(6): 1096-1098
    CAFs Defang NK Cells to Promote Breast Cancer Immunosuppression.
    Mara H Sherman.
      Though NK cells often infiltrate the breast tumor microenvironment, they are frequently described as dysfunctional in this setting, and mechanisms limiting their antitumor cytotoxic potential are unclear. In this issue, Ben-Shmuel and colleagues show that breast cancer-associated fibroblasts interact with NK cells via established ligand-receptor pairs and in turn suppress NK-cell cytolytic potential against cancer cells by acting as decoys. See related article by Ben-Shmuel et al., p. 1247.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0512
  9. Front Immunol. 2025 ;16 1555036
    Targeting myeloid cells in pancreatic ductal adenocarcinoma: from primary tumors to liver metastasis.
    Ruining Gong, Ying Chen, Chang Li, Huan Zhang, Zimin Liu, Qian Yu.
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the malignancies with the highest mortality rates, and outcomes are particularly poor in cases of liver metastasis. Early or recurrent metastatic PDAC significantly worsens patient outcomes and presents substantial clinical challenges. Checkpoint-based immunotherapy has largely been ineffective for most pancreatic cancer patients. This ineffectiveness is not well understood, as clinical trials often involve patients with advanced diseases, such as liver and peritoneal metastases, while most preclinical studies focus on primary tumors. Recent findings indicate that the immunosuppressive tumor microenvironment (TME) is a major obstacle to effective immunotherapy in PDAC, with the metastatic immune microenvironment differing significantly from that of primary tumors. This review explores the distinct immunosuppressive mechanisms at various stages of PDAC progression, including primary tumors, pre-metastatic niches, and metastatic sites. Myeloid cells, such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), play pivotal roles in shaping the TME and suppressing anti-tumor immunity. Particular focus is placed on current clinical immunotherapy strategies targeting myeloid cells, and combinations with conventional chemoradiotherapy, considering contemporary knowledge and future trends. Advancements in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics have provided deeper insights into the molecular intricacies and diversity of PDAC, revealing potential therapeutic targets. Innovative strategies targeting myeloid cells, including CD40 agonists and CSF-1R inhibitors, are being explored to reprogram the TME and enhance the efficacy of immunotherapies.
    Keywords:  immunotherapy; liver metastases; macrophage; monocyte; pancreatic cancer
    DOI:  https://doi.org/10.3389/fimmu.2025.1555036
  10. Front Immunol. 2025 ;16 1582166
    Crosstalk between metabolic reprogramming and microbiota: implications for cancer progression and novel therapeutic opportunities.
    Xingchen Li, Yidi Jia, Yanqing Li, Hu Hei, Songtao Zhang, Jianwu Qin.
      Metabolic reprogramming is a process by which cells adapt to the nutrient microenvironment by regulating energy metabolism. Compared with normal cells, tumor cells tend to undergo metabolic reprogramming, which is one of the hallmarks of concurrent genomic instability, and immune evasion in tumor cells. The microbial community, known as "second genome" of human beings, can cause systemic disease by predisposing cells to tumors, and modulating immune responses to cancer. Metabolic reprogramming and microorganisms can crosstalk with each other in multiple ways to influence various physiological and pathological responses in cancer progression. The products of increased synthesis by tumor cells can reach the intestinal tract via the circulation and act on the microorganisms, promoting mucosal inflammation, causing systemic disorders, and may also regulate the immune response to cancer. In addition, the metabolites of the microorganisms can in turn be transported to the tumor microenvironment (TME) through the systemic circulation and participate in the process of tumor metabolic reprogramming. Different molecular mechanisms related to metabolic reprogramming and microbiota imbalance control the outcome of tumor or anti-tumor responses, depending on the type of cancer, stage of the disease and the TME. In this review, we focus on the fundamental role of metabolic reprogramming in the interaction between microorganisms and cancers and explore the molecular mechanisms by which metabolic reprogramming modulates this complex biological process. This comment aims to provide valuable resources for clinicians and researchers and promote further research in the field.
    Keywords:  anti-tumor therapy; cancer progression; metabolic reprogramming; microbiota; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1582166
  11. Mol Cancer. 2025 Jun 03. 24(1): 161
    Reprogrammed immuno-metabolic environment of cancer: the driving force of ferroptosis resistance.
    Sramana Bhowmick, Saptak Banerjee, Viji Shridhar, Susmita Mondal.
      Ferroptosis, the non-apoptotic, iron-dependent form of cell death is an unavoidable outcome and byproduct of cellular metabolism. Reactive oxygen species generation during metabolic activities transcends to Fe2+-induced lipid peroxidation, leading to ferroptosis. Cancer cells being highly metabolic are more prone to ferroptosis. However, their neoplastic nature enables them to bypass ferroptosis and become ferroptosis-resistant. The capability of cancer cells to reprogram its metabolic activities is one of its finest abilities to abort oxidative damage, and hence ferroptosis. Moreover, the reprogrammed metabolism of cancer cells, also associates with the radical trapping antioxidant systems to enhance the scavenging of ferroptosis and thereby tumor progression. Additionally, the TME, which is an inevitable part and regulator of carcinogenesis, presents an intricate cooperation with tumor metabolism to build an immuno-metabolic environment to regulate the sustenance of cell proliferation and survival. This review focuses on the current understanding of ferroptosis in carcinogenesis and its resistance acquired by cancer cells via several modulators including the radical trapping antioxidant systems, the reprogrammed metabolism, the TME, and intertwined role of cancer metabolism and tumor immunity. The reprogrammed metabolism section further comprehends the functional role of lipids, iron and glucose metabolism against ferroptosis defense separately. The affiliation of TME in ferroptosis regulation is further sectioned with reference to different immune cells present within the TME such as tumor-associated macrophages, tumor-infiltrating neutrophils, myeloid-derived suppressor cells, T-cells, natural killer cells, dendritic cells, and B-cells, modifying the TME in both pro and anti-tumorigenic manner. Subsequently, this review also discusses the convergence of immuno-metabolic environment in ferroptosis regulation, and eventually brings up research gaps in this context providing consequential and significant questions to explore for better understanding of the immuno-metabolic environment's role in driving ferroptosis resistance for anti-cancer treatment progress.
    Keywords:  Ferroptosis; Ferroptosis resistance; Metabolic reprogramming; Reprogrammed immune metabolic environment; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-025-02337-3
  12. Front Immunol. 2025 ;16 1507870
    Emerging immunotherapy and tumor microenvironment for advanced sarcoma: a comprehensive review.
    Hai Huang, Yiwei Fan, Shuling Zhang, Xueli Bai, Xiaonan Wang, Fengping Shan.
      Sarcomas are heterogeneous mesenchymal malignancies classified as soft-tissue sarcomas (STS) and bone sarcomas. Advanced cases respond poorly to standard therapies, highlighting the need for novel strategies. Immunotherapies, including PD-1/PD-L1 inhibitors, adoptive cellular therapies, vaccines, and oncolytic viruses, have shown promise in specific sarcoma subtypes. This review explores these approaches, emphasizing the prognostic significance of immune cells within the tumor microenvironment (TME), such as tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs), and their correlation with clinical outcomes. We also discuss challenges in immunotherapy efficacy, the importance of biomarker-driven personalized therapies, and the potential of a combination regimen with chemotherapy, radiation, and cytokine agents. Overall, this review highlights the evolving role of immunotherapy in advanced sarcomas, the critical influence of the TME, and the need to optimize synergistic treatment approaches to enhance patient outcomes.
    Keywords:  adoptive T cell therapy; immune checkpoint inhibitors; immunotherapy; sarcoma; vaccine
    DOI:  https://doi.org/10.3389/fimmu.2025.1507870
  13. J Transl Med. 2025 Jun 03. 23(1): 623
    Unraveling the role of M2 TAMs in ovarian cancer dynamics: a systematic review.
    Yaping Wang, Caixia Ma, Xiabing Li, Fangfang Yang, Na Wang, Gaili Ji, Qing Liu, Hai Zhu, Shengnan Xu, Hongyu Li.
      Tumor-associated macrophages (TAMs) represent the dominant immune cell subset within the ovarian tumor microenvironment, which exhibits remarkable plasticity. They can readily undergo polarization toward an immunosuppressive M2-like phenotype in response to various factors secreted by tumor cells, playing a pivotal role in ovarian cancer advancement and the development of resistance to chemotherapy. M2 TAMs promote the invasiveness of ovarian cancer cells and their resistance to therapeutic agents through the secretion of numerous tumor-promoting factors, including cytokines, chemokines, enzymes, and exosomes. Furthermore, M2 TAMs significantly contribute to the peritoneal metastasis of cancer cells by aiding in the formation of spheroids and facilitating adhesion at metastatic sites. Concurrently, TAMs can suppress immune responses by interacting with lymphocytes, natural killer cells, and dendritic cells, thereby fostering an immunosuppressive milieu. Extensive research has indicated that M2-like TAMs exert detrimental effects in ovarian tumors, with elevated levels correlating positively with diminished overall survival rates. This review seeks to summarize the existing knowledge regarding the mechanisms through which TAMs affect both the progression of ovarian cancer and the development of chemotherapy resistance, underscoring the necessity for innovative therapeutic approaches aimed at targeting these cells within the tumor microenvironment.
    Keywords:  Chemotherapy resistance; Ovarian cancer; Progression; TAMs; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-025-06643-8
  14. Cancer Pathog Ther. 2025 May;3(3): 183-196
    Tumor-associated macrophages (TAMs): Constructing an immunosuppressive microenvironment bridge for pancreatic ductal adenocarcinoma (PDAC).
    Runjie Liu, Jianang Li, Liang Liu, Wenquan Wang, Jinbin Jia.
      Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with increasing incidences worldwide. The overall 5-year survival rate remains low, underscoring the urgent need for effective therapies. Despite the promising efficacy of immunotherapy for various solid tumors, its benefits for pancreatic cancer have been disappointing. This is largely because of the complex and unique mechanisms of immune evasion inherent in PDAC. Emerging evidence has highlighted the pivotal role of tumor-associated macrophages (TAMs) in facilitating the immune escape of PDAC. TAMs significantly contribute to forming an immunosuppressive microenvironment, which hinders the effectiveness of immunotherapeutic approaches. They achieve this through multiple pathways, including the secretion of cytokines and the promotion or inhibition of multiple immune cells. In this review, we summarized the main pathways through which TAMs form an immunosuppressive microenvironment in PDAC. We also examined the current status and recent progress of immunotherapy strategies that specifically target macrophages. By understanding these mechanisms and exploring targeted therapies, we aimed to shed light on potential avenues for improving the treatment outcomes of this devastating disease.
    Keywords:  Immunosuppression; Macrophages; Pancreatic cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cpt.2024.07.004
  15. Mol Cancer Res. 2025 Jun 06.
    The impact of cancer therapy on the cells and extracellular vesicles of the tumor immune microenvironment.
    Claire Bruno, Andrew Whitcomb, Brooke Pincock, Israel Davila Aleman, Jacob H Neves, Matthew Shaw, Amber Gonda.
      Cancer remains one of the leading causes of morbidity and mortality worldwide, necessitating the development of diverse treatment options to improve patient outcomes. The tumor microenvironment (TME) plays a critical role in determining the efficacy of these different therapies, yet the reciprocal impact of treatment on the TME, particularly the tumor immune microenvironment (TIME), remains incompletely understood. This review investigates the different effects of cancer therapies - chemotherapy, targeted therapy, immunotherapy, and radiotherapy - on immune cells within the TIME and associated extracellular vesicles (EVs). The broader impact on the TME belies a complex and nuanced tumor response. These treatments have been shown to have an impact on the function of various immune cells, influencing their activity to either promote or block tumor growth. Importantly, this review also considers how these therapies play an indirect role in modulating the TIME by influencing the release and contents of EVs, highlighting the significant role that EVs play in intercellular communication within the TIME. By analyzing recent findings, this review aims to provide a comprehensive understanding of how different cancer therapies reshape the TIME. Understanding these dynamic relationships can help pave the way for optimizing existing treatments, developing new therapies, and enhancing patient outcomes.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-25-0101
  16. Discov Oncol. 2025 Jun 04. 16(1): 1003
    Research progress of galectins in glioma.
    Xin-Li Feng, Gang Su, Qiong-Hui Wu, Qi Jia, Zhen-Chang Zhang.
      Galectin, a member of the β-galactoside-binding protein family, is involved in various physiological and pathological processes, including cell adhesion, growth, apoptosis, and immune regulation. Due to its high malignancy, heterogeneity, invasive nature, and resistance to radiotherapy and chemotherapy, no effective treatment has been found for glioma so far. Galectin has been discovered to influence the invasion, migration, angiogenesis, and chemotherapy resistance of glioma, and can also play a significant role in the tumor immunosuppressive microenvironment (TME) by acting on immune cells such as T lymphocytes, macrophages, and myeloid-derived suppressor cells (MDSCs). This review discusses the role of galectin, especially the latest research progress on Gal-1, Gal-3, Gal-8, and Gal-9 in glioma, and proposes the therapeutic potential and challenges of targeting galectin for the treatment of glioma.
    Keywords:  Galectin; Glioma; Immune microenvironment; Target; Therapy
    DOI:  https://doi.org/10.1007/s12672-025-02318-4
  17. Cell Commun Signal. 2025 Jun 05. 23(1): 270
    Combination strategies of gut microbiota in cancer therapy through metabolic reprogramming and immune remodeling.
    Lixuan Wang, Weibo Jiang, Manshi Yang, Quezhu Danzeng, Shiyu Liu, Mengying Cui.
      Over the past decade, there has been a qualitative improvement in the understanding of gut microbiota in cancer development and treatment. Gut microbiota regulates metabolic reprogramming that occurs in the competition between tumor cells and immune cells for essential nutrients in the tumor microenvironment (TME). Besides, gut microbiota dysbiosis is one of the key factors leading to the formation of aging environment, which has many similarities with the TME. Accumulating research findings have demonstrated that gut microbiota enhances the efficacy of cancer therapies by activating the immune system and facilitating the biotransformation of drugs. Other studies also have shown that specific microbial composition is the effective biomarker of drug resistance and toxicity for cancer treatment. Microbiota-directed therapies are being explored intensively for their potential in cancer prevention and treatment. In this review, we summarize the role of gut microbiota in metabolic reprogramming and immune remodeling; provide an overview of the relationship between gut microbiota and the efficacy, resistance, and toxicity of cancer treatment; propose a series of strategies to integrate gut microbiota into cancer treatment, optimizing antitumor effectiveness and reducing side effects.
    Keywords:  Combination cancer therapy; Gut microbiota; Immune remodeling; Metabolic reprogramming; Polymorphic microbiome; The TME
    DOI:  https://doi.org/10.1186/s12964-025-02275-z
  18. Crit Rev Oncol Hematol. 2025 May 29. pii: S1040-8428(25)00173-8. [Epub ahead of print]213 104785
    A new approach to the treatment of ovarian cancer: The application of CAR-T cell therapy.
    Ying Yang, Nan Zhang, Dan Wang, Yun Zhang, Xiaoju Li.
      Ovarian cancer poses a significant threat to women's health, and the limitations of current treatments demand the exploration of new therapeutic solutions. Chimeric antigen receptor (CAR) T cell therapy, a novel form of immunotherapy, has demonstrated substantial efficacy in the treatment of hematological malignancies and holds considerable promise for ovarian cancer treatment. This paper provides a comprehensive review of the application of CAR-T cell therapy in ovarian cancer, with a detailed discussion of therapeutic targets such as mesothelin, MUC16, and FOLR1, along with associated clinical trials. Presently, the application of CAR-T cell therapy in ovarian cancer is confronted with challenges including immunosuppression within the tumor microenvironment (TME), tumor heterogeneity, target-related issues, toxic reactions, and limitations in cell efficacy. To address these challenges, strategies such as modulating immunosuppressive cells, employing dual-target strategies, optimizing target selection and CAR structure, enhancing cell performance, and utilizing combination therapies are proposed. Future research directions are likely to focus on the expansion of combination therapies, the application of nanotechnology, the advanced development of personalized medicine, and the exploration of immune cell diversification. Although CAR-T cell therapy remains in its nascent stages for the treatment of ovarian cancer, ongoing research and technological advancements are anticipated to yield significant breakthroughs, potentially offering more effective treatment options for patients with ovarian cancer.
    Keywords:  CAR-T cell; Combination therapy; Ovarian cancer; Targets; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104785
  19. J Transl Med. 2025 Jun 02. 23(1): 614
    Unraveling the advances of non-coding RNAs on the tumor microenvironment: innovative strategies for cancer therapies.
    Deyang Mu, Bing Han, Hao Huang, Yuchen Zheng, Jungang Zhang, Ying Shi.
      Non-coding RNAs (ncRNAs) are crucial molecules that do not encode proteins but play roles in regulating various biological processes. Recent research highlights that ncRNAs not only control gene expression within cells but also facilitate intercellular communication via exosomes and other carriers. This function is vital in the tumor microenvironment (TME). Our review covers the structure and functions of different ncRNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). We examine how these ncRNAs influence tumor initiation and progression. Additionally, we explore their role in promoting tumor growth or immune evasion by modulating the TME. The potential of using these ncRNAs as therapeutic targets or biomarkers for clinical use is also discussed. As our understanding of ncRNAs grows, the development of new therapies based on ncRNAs is anticipated to offer improved treatment options for cancer patients.
    Keywords:  Cancer therapies; CircRNAs; LncRNAs; MiRNAs; NcRNAs; TME
    DOI:  https://doi.org/10.1186/s12967-025-06629-6
  20. Cytokine. 2025 May 30. pii: S1043-4666(25)00120-6. [Epub ahead of print]192 156973
    Interleukin-enhanced CAR-engineered immune cells in tumor immunotherapy: current insights and future perspectives.
    Min Wang, Zixuan Wang, Guangji Zhang, Jia Fan.
      Despite the remarkable clinical success of chimeric antigen receptor (CAR)-T cell therapy in hematologic malignancies, the therapeutic efficacy of conventional second-generation CAR-T cells in treating solid tumors remains suboptimal, primarily due to three major biological barriers: (1) the immunosuppressive tumor microenvironment (TME), (2) inadequate tumor infiltration capacity, and (3) T cell exhaustion mechanisms. To overcome these limitations, innovative fourth-generation "armored" CAR-T cell platforms have been engineered with integrated cytokine-secreting modules designed to potentiate anti-tumor responses through localized immunomodulation. These advanced cellular therapeutics achieve targeted delivery of various immunostimulatory cytokines directly within the TME, thereby orchestrating three critical therapeutic effects: (I) remodeling of the immunosuppressive niche, (II) enhancement of immune cell persistence, and (III) neutralization of immunosuppressive signaling networks. This comprehensive review systematically examines the translational applications of cytokine-secreting CAR-engineered immune cells, including CAR-T, CAR-NK, and CAR-iNKT cell platforms, in solid tumor immunotherapy, with particular emphasis on multiple classes of immunomodulatory cytokines that enhance cytotoxic potential, promote immune cell survival, and counteract TME-mediated immunosuppression. We critically evaluate preclinical and clinical evidence demonstrating the therapeutic efficacy of cytokine-armed CAR-engineered cells across various tumor models, including hematological malignancies, glioblastoma, and neuroblastoma. Furthermore, this review addresses current translational challenges, particularly cytokine-associated toxicity profiles and innovative strategies for achieving spatiotemporal control of cytokine release, while discussing their potential implications for advancing clinical outcomes in solid tumor immunotherapy.
    Keywords:  Interleukin CAR-T CAR-NK CAR-iNKT proliferation persistence
    DOI:  https://doi.org/10.1016/j.cyto.2025.156973
  21. Cell Death Discov. 2025 May 31. 11(1): 260
    Melanoma innervation, noradrenaline and cancer progression in zebrafish xenograft model.
    Francesca Lorenzini, Johanna Marines, Julien Le Friec, Nam Do Khoa, Maria Angela Nieto, Berta Sanchez-Laorden, Maria Caterina Mione, Laura Fontenille, Karima Kissa.
      The tumor microenvironment, including the peripheral nervous system, plays a key role in regulating tumor biology, from initiation to cancer progression. Here, by modeling aggressive melanoma in larval zebrafish xenografts, we shed light on the dynamics of tumor innervation in the tumor microenvironment (TME). Axonogenesis and dendritogenesis were detected in the neurons surrounding the melanoma niche and neurogenesis was observed in the nearby population of the enteric nervous system. We also demonstrate the crucial role of noradrenaline in promoting melanoma progression with the dissemination and invasion of cancer cells to distant tissues. This zebrafish model will allow to uncover neural markers associated with melanoma progression to help in the design of innovative anti-neurogenic therapies targeting specifically the neuronal signals that regulate melanoma progression.
    DOI:  https://doi.org/10.1038/s41420-025-02523-8
  22. Front Immunol. 2025 ;16 1594009
    Editorial: Vital role of innate immunity in cancer immunotherapy.
    Sibusiso Luthuli, Jiazhu Wu, Xin Zhou.
      
    Keywords:  biomarkers; cancer; complement; immunotherapy; innate immunity; neutrophil extracellular traps; toll-like receptor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1594009
  23. bioRxiv. 2025 May 23. pii: 2025.05.20.650777. [Epub ahead of print]
    Targeting Regnase-1 unleashes CAR T cell antitumor activity for osteosarcoma and creates a proinflammatory tumor microenvironment.
    Adeleye O Adeshakin, Hao Shi, S Scott Perry, Heather Sheppard, Phuong Nguyen, Xiang Sun, Peipei Zhou, Jean-Yves Métais, Trevor Cunningham, K C Anil, Liqing Tian, Vivek Peche, Mollie S Prater, Deanna M Langfitt, Shondra M Pruett-Miller, Jason T Yustein, Giedre Krenciute, Christopher DeRenzo, Hongbo Chi, Stephen Gottschalk.
      Negative regulators of T cell function represent promising targets to enhance the intrinsic antitumor activity of CAR T cells against solid tumors. However, the endogenous immune ecosystem in solid tumors often represents an immunosuppressive therapeutic barrier to CAR T cell therapy, and it is currently unknown whether deletion of negative regulators in CAR T cells reshapes the endogenous immune landscape. To address this knowledge gap, we developed CAR T cells targeting B7-H3 in immune-competent osteosarcoma models and evaluated the intrinsic and extrinsic effects of deleting a potent negative regulator called Regnase-1 (Reg-1). Deletion of Reg-1 not only improved the effector function of B7-H3-CAR T cells but also endowed them with the ability to create a proinflammatory landscape characterized by an influx of IFNγ-producing endogenous T cells and NK cells and a reduction of inhibitory myeloid cells, including M2 macrophages. Thus, deleting negative regulators in CAR T cells enforces a non-cell-autonomous state by creating a proinflammatory tumor microenvironment.
    DOI:  https://doi.org/10.1101/2025.05.20.650777
  24. Front Immunol. 2025 ;16 1601773
    Tumor-infiltrating lymphocytes in cancer immunotherapy: from chemotactic recruitment to translational modeling.
    Fatjona Pupuleku Kraja, Vladimir B Jurisic, Altijana Hromić-Jahjefendić, Nafsika Rossopoulou, Theodora Katsila, Katarina Mirjacic Martinovic, Javier De Las Rivas, Carmen Cristina Diaconu, Árpád Szöőr.
      Tumor-infiltrating lymphocytes (TILs) are a diverse population of immune cells that play a central role in tumor immunity and have emerged as critical mediators in cancer immunotherapy. This review explores the phenotypic and functional diversity of TILs-including CD8+ cytotoxic T cells, CD4+ helper T cells, regulatory T cells, B cells, and natural killer (NK) cells-and their dynamic interactions within the tumor microenvironment (TME). While TILs can drive tumor regression, their activity is often hindered by immune checkpoint signaling, metabolic exhaustion, and stromal exclusion. We highlight TIL recruitment, activation, and polarization mechanisms, focusing on chemokine gradients, endothelial adhesion molecules, and dendritic cell-mediated priming. Special emphasis is placed on preclinical models that evaluate TIL function, including 3D tumor spheroids, organoid co-cultures, syngeneic mouse models, and humanized systems. These provide valuable platforms for optimizing TIL-based therapies. Furthermore, we examine the prognostic and predictive value of TILs across cancer types, their role in adoptive cell therapy, and the challenges of translating preclinical success into clinical efficacy. Emerging technologies such as single-cell sequencing, neoantigen prediction, and biomaterial platforms are transforming our understanding of TIL biology and enhancing their therapeutic potential. Innovative strategies-ranging from genetic engineering and combination therapies to targeted modulation of the TME-are being developed to overcome resistance mechanisms and improve TIL persistence, infiltration, and cytotoxicity. This review integrates current advances in TIL research and therapy, offering a comprehensive foundation for future clinical translation. TILs hold significant promise as both biomarkers and therapeutic agents, and with continued innovation, they are poised to become a cornerstone of personalized cancer immunotherapy.
    Keywords:  adoptive cell transfer; experimental models; immunotherapy; tumor microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2025.1601773
  25. bioRxiv. 2025 May 17. pii: 2025.05.13.653793. [Epub ahead of print]
    Chronic compression drives macrophages toward a pathological pro-tumor state.
    Alice Burchett, Hao Chen, Julian Najera, Scott Howard, Meenal Datta.
      Macrophages comprise a significant portion of the glioblastoma tumor microenvironment and are essential in promoting immunosuppression and tumor progression. Solid tumors such as glioblastoma generate solid stress as they expand, creating a compressive microenvironment for mechanosensitive immune cells including macrophages. Macrophages are known to respond to various mechanical stimuli but have not yet been studied in the context of chronic compression observed in growing tumors. Here, we used a custom in vitro compression system to elucidate the effects of compressive solid stress on murine macrophages. We found that macrophages have significant morphological, transcriptional, metabolic, and functional responses to compression. These changes corresponded to both canonical pro- and anti-inflammatory macrophage states. The gene expression signatures of compressed macrophages more closely resembled those of glioma-associated macrophages known to be associated with worse patient outcomes. These results indicate that compression alone, independent from tumor cell-derived biochemical factors, may contribute to the pathological tumor-associated macrophage phenotype. This could represent a vicious cycle of tumor immunomechanics and mechano-immunology. Targeting solid stress in tumors or the response to solid stress by macrophages may interrupt this feedback loop to help normalize the tumor immune microenvironment and improve glioblastoma response to immunotherapy.
    DOI:  https://doi.org/10.1101/2025.05.13.653793
  26. Front Cell Dev Biol. 2025 ;13 1569337
    Organoids technology in cancer research: from basic applications to advanced ex vivo models.
    Luca Varinelli, Oscar Illescas, Ewelina Julia Lorenc, Davide Battistessa, Marzia Di Bella, Susanna Zanutto, Manuela Gariboldi.
      Patient-derived organoids (PDOs) are tridimensional cultures derived from the stem component of a tissue. They preserve the genetic and phenotypic characteristics of the tissue of origin, and represent valuable in vitro models for drug screening, biomarker discovery, cell therapy and genetic modification. Importantly, PDOs reproduce the tumor behavior and can predict therapeutic responses, making them relevant for clinical applications for personalized therapies. PDOs may also be used for studying the interactions between cancer cells and the tumor microenvironment (TME). These interactions are driven by biochemical factors released by the cells, and biomechanical events such as the remodeling of the extracellular matrix (ECM). In recent years, it has become evident that the interactions between cancer cells and the TME have an impact on tumor development and on the efficacy of cancer therapy Therefore, targeting both tumor cells and the TME may improve patient response to treatment. Most PDO culture protocols are limited to epithelial cells. However, recent advances such as use of decellularized ECM (dECM) scaffolds have allowed for the development of in vivo-like environments that host diverse cell types, both normal and pathological, in a tridimensional (3D) manner that closely mimics the complexity of the TME. dECM-based models effectively replicate the interactions between tumor cells, ECM and the microenvironment, are easy to analyze and adaptable for drug testing. By incorporating TME components and therapeutic agents, these models offer an advanced platform for preclinical testing.
    Keywords:  cancer organoids; decellularized matrix; drug screening; ex vivo cancer models; extracellular matrix (ECM); personalized therapy
    DOI:  https://doi.org/10.3389/fcell.2025.1569337
  27. Cancer Lett. 2025 Jun 03. pii: S0304-3835(25)00417-3. [Epub ahead of print] 217850
    Pan-cancer analysis reveals multifaceted roles of nonmyelinating Schwann cells in gastrointestinal cancers.
    Hui Li, Luju Jiang, Shan Zhang, Xiaocao Miao, Shu-Heng Jiang.
      Cancer neuroscience has emerged as a pivotal interdisciplinary field, offering transformative insights into tumor progression mechanisms. Nonmyelinating Schwann cells (NMSCs), integral yet understudied components of the tumor microenvironment (TME), exhibit complex roles in modulating tumor malignancy. Here, we employed deconvolution algorithms to quantify NMSC enrichment by leveraging bulk RNA-seq data. By integrating multi-omics and single-cell strategies along with comprehensive bioinformatics analyses, we delineated NMSC-mediated regulatory networks and their functional impact on gastrointestinal tumors. NMSC enrichment strongly correlated with core cancer hallmarks, notably "Activating invasion and metastasis" and "Inducing angiogenesis". Immune profiling revealed NMSCs as multifaceted regulators of the TME: positively associated with myeloid-derived suppressor cells, natural killer cells, and regulatory T cells, but inversely correlated with CD56dim NK cells, monocytes, and neutrophils. Genomic analyses uncovered nuanced associations between NMSC abundance and somatic mutations, copy number variation, and methylation patterns, while microRNA mapping highlighted NMSC-specific networks. Single-cell resolution analysis demonstrated that NMSCs engage epithelial cells and fibroblasts via extracellular matrix-centric signaling axes. Collectively, our findings establish NMSCs as multifaceted TME orchestrators, providing mechanistic rationale for NMSC-targeted diagnostic biomarkers and stromal reprogramming therapies in precision oncology.
    Keywords:  Bioinformatics analysis; Multi-omics analysis; Pancreatic cancer; Peripheral glial cells; Prognostic value
    DOI:  https://doi.org/10.1016/j.canlet.2025.217850
  28. Front Immunol. 2025 ;16 1530301
    Recent advances in regulatory immune cells: exploring the world beyond Tregs.
    Peng Shi, Yi Yu, Hongwei Xie, Xiaofang Yin, Xue Chen, Yongfei Zhao, Hai Zhao.
      Regulatory immune cells are pivotal in maintaining immune homeostasis and modulating immune responses to prevent pathologies. While T regulatory cells (Tregs) are extensively recognized for their immunosuppressive roles, emerging subsets of regulatory cells, including regulatory CD8+ cells (CD8+Tregs) regulatory B cells (Bregs), myeloid-derived suppressor cells (MDSCs), regulatory dendritic cells (DCregs), regulatory innate lymphoid cells (ILCregs), and regulatory natural killer cells (NKregs), are garnering increased attention. This review delves into the phenotypic characteristics, mechanisms of action, and immune-regulatory functions of these lesser-known but crucial immune cell subsets. The review provides a comprehensive examination of each cell type, detailing their origins, unique functionalities, and contributions to immune homeostasis. It emphasizes the complex interplay among these cells and how their coordinated regulatory activities influence immune responses in diverse pathological and therapeutic contexts, including autoimmunity, cancer immunotherapy, chronic inflammation, and transplant tolerance. By unraveling these mechanisms, the review outlines novel therapeutic avenues, such as targeting these regulatory cells to modulate immune activity and enhance precision medicine approaches. The future of immunotherapy and immune modulation lies in leveraging the expanded knowledge of these regulatory immune cells, presenting challenges and opportunities in clinical applications.
    Keywords:  Bregs; CD8+ Tregs; DCregs; ILCregs; MDSC; NKregs; Tregs
    DOI:  https://doi.org/10.3389/fimmu.2025.1530301
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