bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–06–22
29 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Progress of Traditional Chinese Medicine in Regulating Immune Cell in the Tumor Microenvironment of Triple-Negative Breast Cancer.
  2. Dual Roles of GM-CSF in Breast Cancer: Immunomodulation and Therapeutic Implications.
  3. Breast cancer exosomes: Managing macrophage polarization and immune regulation in the tumor microenvironment.
  4. Heterogeneity of tumor-associated macrophages in colorectal cancer: Origins, classification, and immunotherapeutic implications.
  5. The role of tumor-associated endothelial cells in malignant progression and immune evasion of liver cancer.
  6. Targeting the hippo pathway as a potential regulator of immune checkpoints in cancer immunotherapy.
  7. Evolving role for eosinophils in cancer: from bench to bedside.
  8. Cholesterol metabolism reprogramming in multiple myeloma: examining its specificity and impact on the immune microenvironment.
  9. Extracellular matrix dynamics in tumor immunoregulation: from tumor microenvironment to immunotherapy.
  10. T cell subsets in cervical cancer tumor microenvironment: advances and therapeutic opportunities.
  11. The dynamic duo: How tumor-associated macrophages and tumor cells team up in cholangiocarcinoma.
  12. Targeting metabolic reprogramming to overcome immune tolerance in melanoma immunotherapy.
  13. The role of tumor microenvironment and immune cell crosstalk in triple-negative breast cancer (TNBC): Emerging therapeutic opportunities.
  14. NK cell activity in the tumor microenvironment.
  15. Cancer-associated fibroblasts in clear cell renal cell carcinoma: functional heterogeneity, tumor microenvironment crosstalk, and therapeutic opportunities.
  16. Osteosarcoma immune microenvironment: cellular struggle and novel therapeutic insights.
  17. Cyclophilin J Reprograms Tumor-associated Macrophages to Exert an Anti-tumor Effect in Liver Cancer.
  18. Dipeptidyl peptidase-4 in the tumor microenvironment of the digestive system: Molecular mechanisms and therapeutic targets.
  19. MicroRNA-7 as a multifaceted regulator of tumor glycolytic metabolism: Mechanistic insights and therapeutic perspectives.
  20. Editorial: The tumor microenvironment and immunotherapy for head and neck tumors.
  21. The tumor microenvironment's role in the response to immune checkpoint blockade.
  22. NDRG1-Driven Lactate Accumulation Promotes Lung Adenocarcinoma Progression Through the Induction of an Immunosuppressive Microenvironment.
  23. Lactate metabolism reprogramming in PDAC: Potential for tumor therapy.
  24. Gut Microbiota Reshapes the Tumor Microenvironment and Affects the Efficacy of Colorectal Cancer Immunotherapy.
  25. Modulation of Chronic Cytokine Dysregulation in Cervical Cancer: Potential Biomarkers and Therapeutic Targets.
  26. Heterogeneous tissue-specific macrophages orchestrate metastatic organotropism of breast cancer: implications for promising therapeutics.
  27. Exosomes in hypoxia: generation, secretion, and physiological roles in cancer progression.
  28. Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications.
  29. Metabolic Regulation of cGAS-STING Signaling in the Tumor Microenvironment: Dual Immune Roles and Therapeutic Implications.
  1. Integr Cancer Ther. 2025 Jan-Dec;24:24 15347354251349824
    Progress of Traditional Chinese Medicine in Regulating Immune Cell in the Tumor Microenvironment of Triple-Negative Breast Cancer.
    Tao He, Silin Yu, Chaoyan Wu.
      Limitations in the therapies of triple-negative breast cancer, the strongest invasive subtype of breast cancer, have led to unsatisfactory clinical outcomes for patients. The efficacy of immunotherapy, an emerging treatment choice for triple-negative breast cancer, is highly related to the functional expression of each immune cell in the tumor immune microenvironment. Therefore, improving the immune response of immune cells in the tumor immune microenvironment is beneficial to enhance the effects of immunotherapy for triple-negative breast cancer clinically. There is now growing evidence that the active ingredients in traditional Chinese medicine, especially herbal medicine can influence the correlation of 2 major immune cell subpopulations in the tumor microenvironment of triple-negative breast cancer: tumor-infiltrating lymphocytes (T lymphocytes, B lymphocytes, Natural killer cells) and tumor-associated myeloid cells (macrophages, myeloid-derived suppressor cells, dendritic cells, neutrophils) expression of immune effect. This suggests that traditional Chinese medicine can effectively improve the immunosuppressive state of tumor microenvironment and enhance the effects of clinical immunotherapy for triple-negative breast cancer.
    Keywords:  immune cells; immunosuppression; traditional Chinese medicine; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.1177/15347354251349824
  2. Crit Rev Oncol Hematol. 2025 Jun 12. pii: S1040-8428(25)00192-1. [Epub ahead of print] 104804
    Dual Roles of GM-CSF in Breast Cancer: Immunomodulation and Therapeutic Implications.
    Yuxuan Guo, Yingya Hu, Da Huang, Jiangnan Yang, Shujun Fu, Xiyun Deng, Jun Long, Jie Wang, Yian Wang.
      Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor secreted by immune and non-immune cells. By binding to specific receptors on target cell surfaces, GM-CSF promotes hematopoiesis, activating immune cells, modulating inflammatory responses, participating in tissue repair, and regulating anti-tumor immunity. Breast cancer is the most prevalent malignancy among women worldwide and the leading cause of cancer-related mortality in females. The pathogenesis of breast cancer is complex, with the tumor microenvironment (TME) playing a pivotal role in disease initiation and progression. The TME comprises malignant tumor cells, immune cells, and stromal cells, where oncogenic mutations in malignant cells drive carcinogenesis and remodel the functionality of surrounding non-malignant cells through intercellular communication molecules, such as cytokines, chemokines, and extracellular vesicles, thereby promoting or suppressing tumor progression. Beyond its direct effects on tumor cells, GM-CSF exhibits dual roles in the TME: On one hand, it exerts anti-tumor immune effects by activating immune cells, enhancing antigen presentation capacity, and improving tumor vaccine efficacy; on the other hand, it may promote the activation of tumor-associated macrophages, tumor-associated neutrophils, and myeloid-derived suppressor cells, thereby suppressing immune responses and facilitating tumor growth and metastasis. This review systematically summarizes the regulatory roles of GM-CSF in breast cancer progression based on its structure and biological functions, and explores its therapeutic potential through various strategies including vaccine development, combination therapies, and nanoparticle-based delivery systems. These insights may provide novel perspectives for future mechanistic investigations and clinical applications of GM-CSF.
    Keywords:  Breast cancer; Dual role; Granulocyte-macrophage colony-stimulating factor; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104804
  3. Semin Oncol. 2025 Jun 19. pii: S0093-7754(25)00057-0. [Epub ahead of print]52(4): 152365
    Breast cancer exosomes: Managing macrophage polarization and immune regulation in the tumor microenvironment.
    Suleiman Ibrahim Mohammad, Ehab Yassen Theab, Asokan Vasudevan, Ashok Kumar Bishoyi, Suhas Ballal, Hussein Riyadh Abdul Kareem Al-Hetty, Aman Shankhyan, Anupria A, Rajashree Panigrahi, Hatif Abdulrazaq Yasin.
      Exosomes are sub-150 nm extracellular vesicles mediating intercellular messaging in breast cancer's complex tumor microenvironment (TME). Produced by both tumor cells and their stroma components, these vesicles excrete various biomolecules, such as microRNAs (miRNAs), proteins, lipids, and even DNA fragments, enabling a functional exchange of information among cells. In breast cancer, different studies indicate a significant role of exosome-mediated signaling in modulating the phenotype of tumor-associated macrophages (TAMs), mainly polarizing them toward an M2-like phenotype, further supporting the potentiality for tumor-promoting functions. This review will detail the diverse roles of breast cancer-derived exosomes and macrophage polarization and elaborate on their recognized pathways by which these vesicles casually alter the macrophage phenotype. In our discussion, we take a broad detour to deeply examine the unique molecular accessories delivered by breast cancer exosomes. In particular, we discuss the miRNAs suppressed by M1-associated gene expression and those endowing M2-related pathways with abilities, and we cover the proteins that activate pathways like the STAT3 and NF-κB pathways in macrophages. This review will also address the relevance of mechanistic issues to clinical manifestation in exosome-mediated macrophage polarization in breast cancer. Finally, targeting exosome-mediated macrophage polarization as a promising strategy to enhance antitumor immunity in conjunction with improving breast cancer outcomes is deliberated.
    Keywords:  Breast cancer; Exosome; Immune cell; Macrophage polarization; Pathogenesis
    DOI:  https://doi.org/10.1016/j.seminoncol.2025.152365
  4. Pathol Res Pract. 2025 Jun 12. pii: S0344-0338(25)00275-4. [Epub ahead of print]272 156082
    Heterogeneity of tumor-associated macrophages in colorectal cancer: Origins, classification, and immunotherapeutic implications.
    Yuna Li, Zhaohui Huang, Yuan Yin.
      Tumor microenvironment (TME) plays an important role in the occurrence, progression, and therapeutic response of malignant tumor. As the main immune cells in TME, tumor-associated macrophages (TAMs) are considered to be potential key targets for cancer diagnosis and treatment. However, the functional roles and clinical significance of TAMs in colorectal cancer (CRC) remains controversial. These controversies may stem from the dynamic changes in TME and the high heterogeneity of TAMs. In this review, we systematically explore the sources, classification, identification methods and clinical significance of TAM heterogeneity in CRC. We also summarize current therapeutic approaches targeting TAMs and their limitations. In addition, differences in the function of TAMs in different stages and subtypes of CRC were analyzed, highlighting their interactions with other immune cells and signaling pathways. It suggests that developing novel therapeutic strategies based on TAM heterogeneity holds promise for advancing precision monitoring and treatment of CRC, and promote the further development of tumor immunotherapy.
    Keywords:  Colorectal cancer; Heterogeneity; Tumor associated macrophages; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.prp.2025.156082
  5. Int Immunopharmacol. 2025 Jun 12. pii: S1567-5769(25)01003-3. [Epub ahead of print]161 115013
    The role of tumor-associated endothelial cells in malignant progression and immune evasion of liver cancer.
    Shuangpeng Pu, Tianguang Liu, Yuan Gao, Zhenyu Wu, Sulai Liu.
      Recent studies have revealed that the malignant progression of hepatocellular carcinoma (HCC) not only stems from tumor cell-intrinsic genetic alterations but is dynamically regulated by the tumor microenvironment (TME). As a pivotal component of TME, tumor-associated endothelial cells (TECs) critically drive HCC progression through dual mechanisms of vascular abnormality and immune modulation. TECs establish a pro-tumorigenic niche by constructing disordered vascular networks while concurrently secreting immunosuppressive factors that induce immune cell dysfunction. This review systematically examines the molecular mechanisms underlying the dynamic transition from hepatic endothelial cells to TECs, identifies key TEC subtypes mediating tumor angiogenesis and immune evasion, and elucidates their crosstalk with immunosuppressive components. Additionally, we highlight TEC-specific biomarkers associated with clinical HCC progression and synthesize current clinical trials targeting TEC-mediated pathways. These findings provide novel insights for developing precision therapies that disrupt the TEC-TME-immune axis in HCC.
    Keywords:  Hepatocellular carcinoma; Immunosuppressive; Therapeutic approaches; Tumor microenvironment; Tumor progression; Tumor-associated endothelial cells
    DOI:  https://doi.org/10.1016/j.intimp.2025.115013
  6. Int Immunopharmacol. 2025 Jun 14. pii: S1567-5769(25)01057-4. [Epub ahead of print]161 115067
    Targeting the hippo pathway as a potential regulator of immune checkpoints in cancer immunotherapy.
    Yu-Ying Meng, Xin Chang, Si-Si Cao, Ping Ma, Yi Ou-Yang, Min Dong.
      The Hippo pathway is a conserved signaling cascade in mammals, known for its critical role in regulating cellular functions, including cell growth, differentiation, and organ size. These functions are largely mediated by the transcriptional effectors YAP and TAZ, which regulate gene expression through interactions with TEAD family transcription factors. Aberrant Hippo pathway signaling has been implicated in various aspects of cancer progression, including tumorigenesis, invasion and metastasis. This review explores the Hippo pathway has been implicated in the regulation of immune checkpoint (IC) expression and the role of the Hippo pathway in the tumor microenvironment (TME). Specifically, the Hippo pathway regulates the TME by influencing T-cell function, myeloid-derived suppressor cell (MDSC) activity, and macrophage polarization and recruitment. Furthermore, we also discuss how the Hippo pathway regulates immune checkpoint inhibitors (ICIs) and its potential for enhancing immunotherapy efficacy while reducing associated adverse effects.
    Keywords:  Genetic biomarker,immunotherapy; Hippo pathway; Immune checkpoint inhibitors; cancer
    DOI:  https://doi.org/10.1016/j.intimp.2025.115067
  7. Trends Cancer. 2025 Jun 12. pii: S2405-8033(25)00131-1. [Epub ahead of print]
    Evolving role for eosinophils in cancer: from bench to bedside.
    S Grisaru-Tal, E A Jacobsen, A Munitz.
      Eosinophils are increasingly recognized as important immune cells in the tumor microenvironment (TME). Recent technological advancements reveal their heterogeneity and complex context-dependent activities including the ability to elicit pro- or anti-tumorigenic effects. For instance, they can mediate cytotoxicity via highly eosinophil-specific granule proteins and reactive oxygen species, and contribute to antitumor immunity by interacting with various cells including T cells. Clinically, eosinophilia is often observed following various treatments including immunotherapy, where they may be beneficial for therapy. This Review explores eosinophil recruitment, immune interactions, therapeutic potential and methods for studying their activity. Understanding the role of eosinophils in the TME may lead to new therapeutic strategies and position them as targets or biomarkers in precision oncology.
    Keywords:  cancer; eosinophils; immune checkpoint blockade; inflammation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2025.05.005
  8. Am J Cancer Res. 2025 ;15(5): 2004-2021
    Cholesterol metabolism reprogramming in multiple myeloma: examining its specificity and impact on the immune microenvironment.
    Hongtao Teng, Feifei Wang, Hairui Liu, Xiaolei Zhang.
      Multiple myeloma (MM) represents a malignancy within the hematological system, in which the reprogramming of cholesterol metabolism plays a pivotal role in its pathogenesis. This review focuses on the specificity of cholesterol metabolism abnormalities in the diagnosis of MM and their implications for the immune microenvironment, aiming to provide new perspectives for both diagnosis and treatment of MM. The expression changes of cholesterol metabolism-related genes (CMGs), such as ANXA2 and CHKA, closely correlate with the prognosis of MM. These CMGs are linked not only to clinical parameters, including the number of transplants and the International Staging System, but also to tumor incidence, progression, and treatment resistance. Consequently, they offer new biological markers for both the prognosis assessment and therapeutic strategies for MM. In terms of the immune microenvironment, reprogramming of cholesterol metabolism significantly influences tumor-infiltrating immune cells (TIICs), including T lymphocytes, B lymphocytes, tumor-associated macrophages (TAMs), dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs). Moreover, the cholesterol metabolite 25-hydroxycholesterol (25-HC) enhances the activity of immunosuppressive macrophages by modulating lysosomal AMPK activation and metabolic reprogramming, thus presenting a new metabolic target for tumor immunotherapy. The regulatory effects of cholesterol metabolism on MDSCs are also noteworthy; these cells promote tumor progression by inhibiting T-cell responses. High-fat diets and obesity can induce the accumulation of MDSCs, where molecules involved in the cholesterol metabolic pathway, such as the synthase CYP27A1 for 27-hydroxycholesterol (27-HC), have been associated with poor prognoses in ovarian cancer. Genetic knockout of this enzyme significantly inhibits tumor progression. Regarding the diagnostic specificity of cholesterol metabolism abnormalities, these changes present novel biomarkers for the early diagnosis and therapeutic monitoring of MM. Analyzing the correlation between immune cell proportions in the tumor microenvironment and lipid metabolism genes has unveiled potential links between cholesterol metabolism and immune responses, paving the way for precision medicine in MM. Thus, the reprogramming of cholesterol metabolism in MM offers a multidimensional and interdisciplinary research avenue. Future studies need to delve deeper into the specific mechanisms through which cholesterol metabolism contributes to MM development and leverage these findings to formulate new therapeutic strategies, ultimately improving outcomes for MM patients.
    Keywords:  Multiple myeloma; cholesterol metabolism reprogramming; diagnostic specificity; immune microenvironment
    DOI:  https://doi.org/10.62347/CCCT1933
  9. J Hematol Oncol. 2025 Jun 19. 18(1): 65
    Extracellular matrix dynamics in tumor immunoregulation: from tumor microenvironment to immunotherapy.
    Qin Hu, Yifei Zhu, Jie Mei, Ying Liu, Guoren Zhou.
      The extracellular matrix (ECM), closely linked to the dynamic changes in the tumor microenvironment (TME), plays a critical role in modulating tumor immunity. The dual role of the ECM in tumor progression, encompassing both promotion and inhibition, is attributed to its components influencing immune cell activation, migration, and infiltration. This mechanism is intricately connected with the efficacy of immunotherapies. Currently, there is limited understanding of how ECM remodeling spatially and temporally coordinates with immune checkpoint inhibitors (ICIs) or adoptive cell therapies. Furthermore, strategies to selectively target pathological ECM components while preserving their homeostatic functions urgently require systematic investigation. In this review, we summarize current findings on the interplay between ECM and tumor immune regulation, with a particular focus on how key ECM components contribute to immune modulation. Furthermore, we discuss emerging strategies targeting ECM-related mechanisms to enhance the efficacy of immunotherapies, including approaches that remodel the ECM to improve immune infiltration and strategies that synergize with existing immunotherapies. By integrating these insights, we provide a perspective on leveraging ECM-targeted interventions to overcome immune evasion and optimize cancer immunotherapy outcomes.
    DOI:  https://doi.org/10.1186/s13045-025-01717-y
  10. Front Immunol. 2025 ;16 1612032
    T cell subsets in cervical cancer tumor microenvironment: advances and therapeutic opportunities.
    Weilin Guo, Lan Dai, Lihua Qiu.
      Cervical cancer is the third most common malignancy among Chinese women in both incidence and mortality. Its progression is closely linked to complex interactions among immune cells within the tumor microenvironment (TME). As key components of the immune landscape, different T cell subsets play diverse and dynamic roles in shaping tumor immunity. This review provides a comprehensive overview of the roles of various T cell subsets in the TME of cervical cancer, with a focus on their distribution, functional heterogeneity, dynamic balance, and variations across different pathological subtypes and disease stages. We also highlight the intricate crosstalk between T cells and other immune cells in the TME and discuss recent advances in T cell-related immunotherapies for cervical cancer, including immune checkpoint inhibitors and HPV-targeted vaccines. By elucidating the roles of distinct T cell subsets and relevant immunotherapeutic approaches within the TME, this review provides insights into potential therapeutic targets and approaches for improving cervical cancer treatment and patient outcome.
    Keywords:  T cell; cervical cancer; immune regulation; immunotherapy; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2025.1612032
  11. Hepatology. 2025 Jul 01. 82(1): 1-2
    The dynamic duo: How tumor-associated macrophages and tumor cells team up in cholangiocarcinoma.
    Binbin Li, Sumera I Ilyas.
      
    DOI:  https://doi.org/10.1097/HEP.0000000000001378
  12. Front Immunol. 2025 ;16 1597770
    Targeting metabolic reprogramming to overcome immune tolerance in melanoma immunotherapy.
    Qinchen Wang, Lei Shi, Daoming Shi, Ningzheng Tai, Xu Wang.
      Significant advances in the treatment of melanoma, the most aggressive form of skin cancer, have been achieved via immunotherapy. Despite these improvements, therapeutic resistance remains a formidable challenge, compromising the treatment efficacy and patient outcomes. This review delves into the intricate mechanisms driving immunotherapy resistance in melanoma, emphasizing alterations in key metabolic pathways, changes within the tumor microenvironment, and the critical role of the gut microbiota. This review also examines how metabolic reprogramming supports tumor proliferation and immune evasion, it highlights the impact of extracellular acidification and angiogenic processes on resistance development. By synthesizing current insights, this review emphasizes the importance of targeting these multifaceted interactions to overcome resistance, thereby paving the way for more effective and durable therapeutic strategies in melanoma treatment.
    Keywords:  gut microbiota; immune tolerance; immunotherapy; melanoma; metabolic pathways; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1597770
  13. Cancer Lett. 2025 Jun 15. pii: S0304-3835(25)00432-X. [Epub ahead of print]628 217865
    The role of tumor microenvironment and immune cell crosstalk in triple-negative breast cancer (TNBC): Emerging therapeutic opportunities.
    Hussein Sabit, Amro Adel, Mariam M Abdelfattah, Rehab M Ramadan, Mahmoud Nazih, Shaimaa Abdel-Ghany, Ahmed El-Hashash, Borros Arneth.
      Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by its lack of estrogen, progesterone, and HER2 receptors, leading to limited treatment options and poor prognosis. This review synthesizes current research on the tumor microenvironment (TME) and immune cell crosstalk in TNBC to identify emerging therapeutic opportunities. The TME in TNBC is a complex ecosystem comprising immune cells, fibroblasts, and extracellular matrix components, which significantly influence tumor growth and metastasis. Single-cell RNA sequencing reveals T-cell heterogeneity and identifies prognostic genes. Regulatory T cells (Tregs) play a key role in immunosuppression, with thymidine kinase-1 (TK1) identified as a potential therapeutic target. MUC1-C and CXCL9 modulate the TME, impacting T-cell depletion and macrophage differentiation. Spatial analysis highlights the importance of cell-to-cell interactions in predicting recurrence. Epithelial-mesenchymal transition (EMT) and thermogenesis also influence the TME, while epigenetic modifications, such as HDAC inhibition, can induce pyroptosis and enhance immune cell recruitment. Integrating genomic information with TME analysis is crucial for developing personalized treatments, considering racial disparities in immune infiltration. Emerging therapies targeting immune checkpoints, modulating Treg activity, and inducing pyroptosis hold promise for improving TNBC patient outcomes. Future research should focus on multi-omics data, spatial transcriptomics, and patient-derived models to refine therapeutic interventions.
    Keywords:  (ADC); (AI); (MDSCs); (PARPi); (TME); AR/Scr/Pl3-K; Anti-androgen therapies; Antibody-drug conjugate; Artificial intelligence; Immunotherapy; Myeloid-derived suppressor cells; PARP inhibitors; Prognostic markers; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2025.217865
  14. Front Cell Dev Biol. 2025 ;13 1609479
    NK cell activity in the tumor microenvironment.
    A V Kuznetsova, X A Glukhova, I P Beletsky, A A Ivanov.
      The formation of an immunosuppressive tumor microenvironment (TME) impairs natural killer (NK) cell infiltration and persistence within tumor tissue and significantly diminishes NK-mediated cytotoxicity. This presents a substantial barrier to the efficacy of NK cell therapy in solid tumors. Current strategies aim to overcome immune evasion by enhancing NK cell recognition and cytotoxicity, while promoting their persistence, infiltration, and resistance to the TME. This review focusses on the biophysical characteristics of TME and specific components of the extracellular matrix (ECM) that affect NK cell activity, with the goal of identifying therapeutic approaches to modulate the TME and create a supportive niche for adaptive immune cell function. Advancements in interdisciplinary collaborations integrating oncology, cell biology, physics, engineering, materials science, and nanotechnology are crucial in advancing therapeutic strategies targeting ECM rigidity and mechanotransduction signaling pathways.
    Keywords:  anti-NK cell signaling; extracellular matrix; human natural killer cells; new targets; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2025.1609479
  15. Front Immunol. 2025 ;16 1617968
    Cancer-associated fibroblasts in clear cell renal cell carcinoma: functional heterogeneity, tumor microenvironment crosstalk, and therapeutic opportunities.
    Man Wang, Yuanzhuo Zhao, Kangchun Xu, Chao Liu, Hui Zhong, You Wu, Ke Zhang, Shanzhai Wei.
      Clear cell renal cell carcinoma (ccRCC) progression heavily relies on the immunosuppressive tumor microenvironment (TME). In the ccRCC TME, the cancer-associated fibroblasts (CAFs) drive a self-perpetuating cycle of immune evasion and therapeutic resistance through diverse interactions between cells and molecules. Furthermore, heterogeneous CAFs facilitate tumor growth through metabolic reprogramming and modulate immune suppression by driving the M2 polarization of tumor-associated macrophages (TAMs) and the expansion of regulatory T cells (Tregs), which promote a multilayered immunosuppressive network. In addition, CAFs reshape the mechanical properties of extracellular matrix (ECM), hinder the infiltration of cytotoxic T lymphocytes (CTLs) and further exacerbate immune escape. Moreover, CAF-derived exosomes can confer resistance to chemoradiation therapy. Interleukin-6 (IL-6) secreted by CAFs synergizes with vascular endothelial growth factor (VEGF) to facilitate adaptive resistance to targeted therapy. Emerging therapeutic strategies-including fibroblast activation protein (FAP)-targeted CAR-T cells and transforming growth factor-β (TGF-β) inhibitors-can partially reverse this immunosuppressive property. Combination therapies employing immune checkpoint inhibitors and VEGF antagonists exhibit promising synergistic effects, although the clinical translation remains hampered by CAF heterogeneity, dual functional roles, and the lack of specific biomarkers. Future studies should integrate single-cell sequencing and spatial multi-omics techniques to comprehensively analyze the spatio-temporal dynamic heterogeneity of CAF subpopulations and develop precision treatment strategies based on molecular subtyping, aiming to break the vicious cycle of "CAF-TME-resistance" in ccRCC.
    Keywords:  cancer-associated fibroblasts (CAFs); clear cell renal cell carcinoma (ccRCC); combination immunotherapy; immune evasion; therapy resistance; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2025.1617968
  16. Front Immunol. 2025 ;16 1584450
    Osteosarcoma immune microenvironment: cellular struggle and novel therapeutic insights.
    Yi Zhang, Shasha Jiang, Jing Lv, Wei Feng, Yan Yu, Heping Zhao.
      Recent advances in immunotherapy have shown remarkable success across multiple solid tumor types, revitalizing interest in immune-modulating strategies for osteosarcoma (OS). Within the complex tumor microenvironment (TME), immune cells exhibit dual regulatory roles-exerting critical regulatory influences on both tumorigenesis and disease progression while simultaneously serving as therapeutic targets. Particularly in OS, the dynamic interplay between malignant cells and the unique bone microenvironment manifests through intricate immune cell-mediated crosstalk. This comprehensive review analyzes the paradoxical roles of immune cell subsets in OS pathophysiology, detailing their tumor-promoting versus tumor-suppressing functions. Furthermore, we systematically evaluate recent progress in immune cell-targeted therapeutic approaches, including adoptive cell therapies and macrophage reprogramming strategies. The review encompasses current clinical applications and emerging preclinical innovations, providing valuable insights for optimizing immunotherapeutic approaches in OS management.
    Keywords:  immune cell; immunotherapy; osteosarcoma; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1584450
  17. Int J Biol Sci. 2025 ;21(8): 3776-3790
    Cyclophilin J Reprograms Tumor-associated Macrophages to Exert an Anti-tumor Effect in Liver Cancer.
    Jing Wang, Chen Yao, Qi Zeng, Lixia Peng, Shimeng Zhang, Yizhi Mao, Lingyi Fu, Shuai Chen, Chunjie Sheng.
      The presence of tumor-associated macrophages (TAMs) characterized by an M2-like phenotype sustains a robust immunosuppressive tumor microenvironment (TME), promoting liver hepatocellular carcinoma (LIHC) progression. Here, we find that genetic deletion of cyclophilin J (CYPJ) in mice significantly accelerates the development of liver cancer. Analysis of immune cell infiltration reveals that high expression of CYPJ correlates with an increased proportion of M1-polarized, anti-tumor macrophages and CD8+ T cells in the TME. Mechanistically, we demonstrate that CYPJ interacts with AKT1 and inhibits the PI3K-AKT signaling pathway, which leads to polarization of TAMs toward the anti-tumor M1 phenotype, resulting in a tumor-suppressive effect. Collectively, our findings implicate CYPJ as a novel potential therapeutic target for macrophage-mediated therapy in liver cancer.
    Keywords:  Cyclophilin J (CYPJ); Liver hepatocellular carcinoma (LIHC); Tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.7150/ijbs.113197
  18. Int J Cancer. 2025 Jun 16.
    Dipeptidyl peptidase-4 in the tumor microenvironment of the digestive system: Molecular mechanisms and therapeutic targets.
    Jingting Wang, Lei Zhao, Duo Yun, Haishan Lin, Jing Wang, Bangwei Cao.
      Digestive system cancers represent nearly half of all global cancer cases and are associated with high mortality rates. Although immunotherapy has ushered in a new era for the treatment of digestive system cancers, the complexity and diversity of the immunosuppressive tumor microenvironment (TME) pose significant challenges to effective immunotherapy for digestive tumors. Dipeptidyl peptidase 4 (DPP4), also known as CD26, has garnered considerable attention for its role within the TME, where it plays a crucial role in the initiation and progression of digestive system cancers and serves as a predictive biomarker for certain cancers. Additionally, it is involved in regulating immune responses, angiogenesis, ferroptosis activation, tumor-associated inflammation, neurotransmission, and metastasis. Thus, DPP4 inhibitors play a pivotal role in modulating the intricate tumor ecosystem, contributing to the control of digestive system cancer development. Therefore, a deeper understanding of DPP4's mechanisms in the TME holds promise for establishing essential theoretical frameworks for developing novel treatment strategies for digestive system cancers. This review explores the regulatory role of DPP4 in the TME of digestive system cancers and its clinical implications, aiming to provide insights into potential advancements in oncological therapies.
    Keywords:  digestive system cancer; dipeptidyl Peptidase‐4; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1002/ijc.35500
  19. Pharmacol Res. 2025 Jun 13. pii: S1043-6618(25)00247-6. [Epub ahead of print]218 107822
    MicroRNA-7 as a multifaceted regulator of tumor glycolytic metabolism: Mechanistic insights and therapeutic perspectives.
    Yiling Zhu, Jiayi Zhang, Xu Zhao, Mengmeng Guo, Chao Chen, Ya Zhou, Lin Xu.
      Aberrant glycolysis is a hallmark of tumor and a key oncogenic driver. However, the complex regulatory networks and dynamic signaling interactions governing glycolysis within the tumor microenvironment (TME) remain incompletely understood, posing significant challenges for developing targeted metabolic therapies. MicroRNA-7 (miR-7), a highly conserved non-coding RNA, is broadly expressed across tissues and plays pivotal roles in development, immune regulation, and disease pathogenesis, including tumor. Recent evidence positions miR-7 as a multifaceted regulator of tumor glycolysis, capable of modulating glucose metabolism through diverse mechanisms. miR-7 inhibits glucose uptake and glycolytic flux in tumor cells by directly targeting glucose transporters and glycolytic enzymes. Additionally, it influences key signaling pathways that govern the expression of glycolysis-related genes. Notably, miR-7 regulates the HIF-1α/ENO2 axis and impacts immune checkpoint expression, such as PD-L1, thereby reshaping the immunosuppressive TME and facilitating metabolic-immune crosstalk. These findings underscore the unique role of miR-7 in tumor metabolic regulation and its potential as a therapeutic target. This review provides a comprehensive overview of the molecular mechanisms by which miR-7 modulates tumor glycolysis, offering new insights into tumorigenesis and informing the development of precision oncology strategies. We also highlight unresolved questions and future directions, including the potential of miR-7-based combinatorial approaches targeting metabolic and immune pathways in tumor.
    Keywords:  Clinical therapy; Glycolysis; Metabolic reprogramming; Signaling crosstalk; Tumor microenvironment; miR-7
    DOI:  https://doi.org/10.1016/j.phrs.2025.107822
  20. Front Oncol. 2025 ;15 1606787
    Editorial: The tumor microenvironment and immunotherapy for head and neck tumors.
    Yifan Jiang, Wenyi Yang, Jingzhou Hu, Lei Tao.
      
    Keywords:  head and neck tumor; immune checkpoint inhibitors; immune evasion; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2025.1606787
  21. Nat Cancer. 2025 Jun 13.
    The tumor microenvironment's role in the response to immune checkpoint blockade.
    Konstantinos Aliazis, Anthos Christofides, Rushil Shah, Yao Yu Yeo, Sizun Jiang, Alain Charest, Vassiliki A Boussiotis.
      Beyond cancer cells, the tumor microenvironment (TME) includes cells of the innate and adaptive immune systems but also non-immune cells, such as fibroblasts and endothelial cells. Depending on the cues they receive, infiltrating myeloid cells, such as monocytes, macrophages, dendritic cells and neutrophils, perform immune stimulatory or suppressive functions by educating adaptive immune cells, thereby guiding their responses to cancer cells and cancer treatment, such as immune checkpoint blockade (ICB). The increasing understanding that anti-tumor immunity goes beyond T cells with improved functionality, and the unraveling of resistance mechanisms beyond T cell exhaustion, have renewed interest in non-T cell components of the TME to identify novel therapeutic targets and improve ICB responses. Here, we review immune and non-immune cellular components of the TME that regulate adaptive cell responses and their role in ICB response and resistance.
    DOI:  https://doi.org/10.1038/s43018-025-00986-3
  22. Adv Sci (Weinh). 2025 Jun 20. e01238
    NDRG1-Driven Lactate Accumulation Promotes Lung Adenocarcinoma Progression Through the Induction of an Immunosuppressive Microenvironment.
    Gujie Wu, Hongxia Cheng, Jiacheng Yin, Yuansheng Zheng, Haochun Shi, Binyang Pan, Ming Li, Mengnan Zhao, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Guoshu Bi, Weigang Guo, Lin Wang, Yiwei Huang.
      Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality, with the tumor microenvironment (TME) playing a critical role in its progression. Metabolic reprogramming, particularly lactate accumulation, drives immune suppression within the TME. Utilizing single-cell RNA sequencing (scRNA-seq) of 30 LUAD samples, genome-wide association studies (GWAS) involving 29,863 patients and 55,586 controls, and clinical data from 220 LUAD patients, we identified N-Myc downstream-regulated gene 1 (NDRG1) as a key pathogenic gene in LUAD, strongly associated with tumor progression and poor prognosis. Mechanistic studies revealed that NDRG1 stabilizes lactate dehydrogenase A (LDHA) by inhibiting its ubiquitination, thereby enhancing glycolysis and promoting lactate accumulation. This process fosters immune suppression by inducing M2 macrophage polarization, impairing CD8+ T cell function, and upregulating immunosuppressive genes. Furthermore, histone H3K18 lactylation in macrophages exacerbates this immunosuppressive state. Clinically, elevated NDRG1 expression correlates with increased PD-L1 levels, a higher abundance of immunosuppressive macrophages, and reduced CD8+ T cell infiltration, contributing to immunotherapy resistance. Conversely, low NDRG1 expression is associated with enhanced CD8+ T cell infiltration and improved therapeutic outcomes. Preclinical studies demonstrated targeting NDRG1 suppresses tumor growth, alleviates immune suppression, and boosts anti-PD-L1 efficacy. These findings establish NDRG1 as a critical LUAD regulator and a promising immunotherapy target.
    Keywords:  NDRG1; immunotherapy; lactylation; lung adenocarcinoma; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202501238
  23. Biochim Biophys Acta Rev Cancer. 2025 Jun 11. pii: S0304-419X(25)00115-5. [Epub ahead of print]1880(4): 189373
    Lactate metabolism reprogramming in PDAC: Potential for tumor therapy.
    Fan Gao, Kang Sun, Sicheng Wang, Xiaozhen Zhang, Xueli Bai.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. During tumor progression, metabolic reprogramming plays a crucial role in both tumor proliferation and immune evasion. In PDAC, genetic mutations and environment limitations lead to resulting in increased lactate production through enhanced glycolysis. Elevated glycolysis is a significant metabolic feature in pancreatic cancer, leading to lactate accumulation within both the tumor cells and tumor immune microenvironment. Lactate not only promotes tumor growth and sustains its survival but also has a profound impact on the immune-suppressive phenotype switch of immune cells. Lactate promotes tumor progression through various biological processes. Pharmacological agents targeting lactate generation, accumulation and lactate-related molecular pathways show potential clinical translation value in cancer treatment.
    Keywords:  GPR81; Lactate metabolism; Lactylation; Metabolic reprogramming; PDAC; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189373
  24. Cancer Med. 2025 Jun;14(12): e70994
    Gut Microbiota Reshapes the Tumor Microenvironment and Affects the Efficacy of Colorectal Cancer Immunotherapy.
    Fayuan Wang, Weidong Chen, Yingtian Jia, Tao He, Siyi Wu, Jiahui Xiang, Rui Chen, Qingfeng Jiang, Tengjiang Yu, Yong Lan, Wusheng Li, Liang Ma, Ping He, Shichao Li.
       BACKGROUND: Colorectal cancer (CRC) is among the most prevalent malignant tumors in the digestive system and is the third leading cause of cancer-related mortality. In recent years, immunotherapy has markedly enhanced the objective response and survival rates for CRC patients. However, the therapeutic efficacy of immunotherapy remains insufficient for the majority of proficient mismatch repair (pMMR) CRC patients, with 20% to 30% of deficient mismatch repair (dMMR) patients demonstrating poor responses or developing drug resistance. Increasing evidence underscores the critical role of intestinal microorganisms in modulating the effectiveness of immunotherapy, particularly in regulating the tumor microenvironment (TME).
    METHODS: This review investigates the differences in intestinal microbiota and TME between dMMR and pMMR CRC. It explores how intestinal microbial communities influence TME components, including immune cells, macrophages, and fibroblasts, thereby impacting the response to immunotherapy.
    CONCLUSION: Intestinal microorganisms play a critical role in the effectiveness of immunotherapy. Variations in intestinal microbiota and the TME among patients with different mismatch repair deficiencies can significantly influence the efficacy of immune checkpoint inhibitors. Modulating the intestinal microbiota has the potential to enhance the therapeutic response of CRC to immunotherapy.
    Keywords:  colorectal cancer; gut microbiota; immune checkpoint inhibitors(ICIs); immunotherapy; tumor microenvironment (TME)
    DOI:  https://doi.org/10.1002/cam4.70994
  25. Cancer Manag Res. 2025 ;17 1113-1126
    Modulation of Chronic Cytokine Dysregulation in Cervical Cancer: Potential Biomarkers and Therapeutic Targets.
    Emmanuel Ifeanyi Obeagu.
      Cervical cancer progression is not solely driven by persistent human papillomavirus (HPV) infection but is profoundly influenced by the local immune microenvironment, particularly chronic cytokine imbalances. Unlike the acute cytokine storms observed in infections or sepsis, cervical cancer is characterized by a persistent, low-grade, "smoldering inflammatory response" that fuels tumor initiation, progression, and immune evasion. Pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, and IL-8 sustain a tumor-supportive milieu, promoting angiogenesis, epithelial-mesenchymal transition, and resistance to apoptosis, while immunosuppressive cytokines like IL-10 and TGF-β dampen anti-tumor immune responses and facilitate immune escape. This review explores chronic cytokine dysregulation in cervical cancer, examining how the prolonged, dysregulated cytokine network shapes the tumor microenvironment, remodels stromal interactions, and influences immune cell recruitment and function. We highlight key cytokines involved in these processes and discuss their clinical significance as potential diagnostic, prognostic, and predictive biomarkers. Understanding these sustained inflammatory processes is critical because they represent a distinct biological landscape compared to acute inflammatory reactions and offer unique windows for therapeutic intervention. The paper reviewed emerging therapeutic strategies targeting these chronic cytokine pathways, including cytokine blockade, immune modulation, and combination approaches integrating immunotherapies or nanomedicine. Addressing chronic cytokine dysregulation holds promise for improving cervical cancer management and patient outcomes.
    Keywords:  biomarkers; cervical cancer; cytokine storm; inflammation; therapeutic targets
    DOI:  https://doi.org/10.2147/CMAR.S527913
  26. J Transl Med. 2025 Jun 20. 23(1): 692
    Heterogeneous tissue-specific macrophages orchestrate metastatic organotropism of breast cancer: implications for promising therapeutics.
    Cenzhu Wang, Pinchao Fan, Yu Zhou, Meican Ma, Haowei Zhong, Lei Liu, Qin Chen, Kun Xu.
      Compelling evidences have manifested that breast cancer cells prefer to metastasize to certain distant organs, including brain, lung, bone and liver. According to the canonical "seed and soil" theory, this prominent biological behavior, termed as metastatic organotropism, involves intricate interactions between breast cancer cells (the "seeds") and specific residents in the tumor microenvironment (the "soil"), initiating from pre-metastatic niche formation to metastatic outgrowth. Recently, multifaceted heterogeneity of tissue-specific macrophages (TSMs) and their roles played in organotropic metastases of breast cancer are incrementally unveiled. Herein, we decipher multiple diversities of TSMs, including evolvement, profiles, functions and metabolic characteristics under different polarization states. Further, we elaborate on bidirectional effects of TSMs on metastatic organotropism of breast cancer (both to the "seeds" and "soil"), and unearth underlying signaling pathways based on updated mechanistic researches. Lastly, we compile a series of clinical trials, hoping to illuminate promising TSM-targeting therapies against breast cancer organotropic metastases.
    Keywords:  Breast cancer; Metastatic organotropism; Seed and soil; Tissue-specific macrophage; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-025-06660-7
  27. Front Immunol. 2025 ;16 1537313
    Exosomes in hypoxia: generation, secretion, and physiological roles in cancer progression.
    Yufeng Mu, Mengrui Yang, Jingyang Liu, Yan Yao, Huimin Sun, Jing Zhuang.
      The hypoxic microenvironment represents a universal hallmark feature of most solid tumors, profoundly shaping cancer progression through multifaceted mechanisms. Acting as nanoscale molecular envoys, exosomes transport oncogenic cargoes (including non-coding RNAs, mutated proteins, and metabolites) to reprogram stromal cells, prime pre-metastatic niches, and establish tumor-host metabolic symbiosis. Their lipid bilayer architecture ensures the protection of labile hypoxia-responsive factors, positioning them as critical amplifiers of intercellular crosstalk within the tumor microenvironment. Despite significant advances, critical gaps persist in understanding the spatiotemporal regulation of exosomal release under hypoxia, particularly the organ-specific variations in hypoxic exosome signatures revealed by single-vesicle analyses. This review synthesizes recent advances in the intricate interplay between hypoxia and exosomes, emphasizing hypoxia-related signaling pathways that directly modulate exosome biogenesis and indirectly activate hypoxia-associated microenvironmental remodeling, alongside their distinct regulatory effects on exosomal cargo composition. Furthermore, it delineates the pivotal role of hypoxia-specific exosomes in driving cancer malignancy, including metastatic dissemination, immune evasion, and therapy resistance. By integrating molecular mechanisms with clinically actionable insights, this work establishes a translational framework for targeting the hypoxic exosome network in precision oncology, offering strategic references for biomarker discovery and therapeutic development.
    Keywords:  TME (tumor microenvironment); exosomes; hypoxia; oncogenic cargoes; tumor
    DOI:  https://doi.org/10.3389/fimmu.2025.1537313
  28. Int J Med Sci. 2025 ;22(11): 2852-2876
    Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications.
    Xinyi Chen, Mu Yang, Lu Wang, Jingyao Tu, Xianglin Yuan.
      Metabolic reprogramming enables cancer cells to adapt to the tumor microenvironment, facilitating their survival, proliferation, and resistance to therapy. While glucose has long been considered the primary substrate for cancer cell metabolism, recent studies have highlighted the role of fructose as an alternative carbon source. Fructose metabolism, particularly through key enzymes such as ketohexokinase (KHK) and aldolase B (ALDOB), along with the fructose transporter GLUT5, supports tumor growth, metastasis, and therapeutic resistance. This review explores the mechanisms by which fructose metabolism influences cancer progression, focusing on its metabolic pathways and its impact on the tumor microenvironment. By promoting glycolysis, lipid biosynthesis, and nucleotide production, fructose metabolism enhances the metabolic adaptability of cancer cells, especially in glucose-deprived conditions. A comprehensive understanding of these processes offers potential insights into therapeutic strategies targeting fructose metabolism for cancer treatment. However, further studies are required to fully elucidate the complex role of fructose in various malignancies.
    Keywords:  aldolase; fructose metabolism; glucose transporter; ketohexokinase; metabolic reprogramming; tumor metabolism
    DOI:  https://doi.org/10.7150/ijms.108549
  29. Cytokine Growth Factor Rev. 2025 Jun 06. pii: S1359-6101(25)00074-7. [Epub ahead of print]
    Metabolic Regulation of cGAS-STING Signaling in the Tumor Microenvironment: Dual Immune Roles and Therapeutic Implications.
    Yong Wu, Wen-Min Lu, Qian-Ru Cui, Jing Zhou, Guo-Dong Lu.
      The cGAS-STING pathway, a cytosolic DNA-sensing mechanism, plays a context-dependent pivotal role in tumor immunity and tumor microenvironment (TME) remodeling. Acute activation of this pathway promotes type I interferon (IFN-I) and pro-inflammatory responses, including dendritic cell (DC) maturation and cytotoxic T cell recruitment, whereas chronic stimulation paradoxically drives immunosuppression and tumor progression through mechanisms such as PD-L1 upregulation and regulatory T cell activation. Tumor metabolic reprogramming-encompassing hypoxia, glycolysis, Krebs cycle metabolites, amino acids, lipids, TME acidity and redox species -emerges as a critical modulator of cGAS-STING activity. For instance, hypoxia suppresses cGAS-STING via TET1-mediated induction of miR-25 and miR-93, while oxygen supplementation reactivates antitumor immunity. Glucose flux exerts dual regulatory effects: NSUN2-dependent TREX2 stabilization limits cytosolic DNA accumulation, whereas glycolysis ATP fuels STING-dependent DC activation. Beyond tumor cells, cGAS-STING signaling in cancer-associated fibroblasts promotes chemoresistance via DNA damage repair, and endothelial STING activation normalizes tumor vasculature to alleviate TME hypoxia and improve T cell infiltration. Current therapeutic strategies prioritize isoform-specific agonists (e.g. cyclic dinucleotides like ADU-S100; non-CDNs like diABZI) and precision delivery systems, such as nanoparticles and engineered bacteria, to address challenges like short half-life and systemic toxicity. Synergistic approaches-including ACLY inhibition to amplify mitochondrial DNA release or pH-responsive nanoparticles co-delivering STING/TLR4 agonists-enhance efficacy when combined with checkpoint inhibitors and radiotherapy. However, the pathway's dual roles, particularly its tumor-promoting effects in advanced malignancies, necessitate context-dependent modulation. This review integrates preclinical insights and clinical trial data to outline strategies for harnessing cGAS-STING signaling in cancer immunotherapy while balancing its immunostimulatory and immunosuppressive outputs.
    Keywords:  CGAS-STING; Metabolic reprogramming; Microenvironment remodeling; Therapeutic agonists; Tumor immunity
    DOI:  https://doi.org/10.1016/j.cytogfr.2025.06.002
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