bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–04–13
38 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives.
  2. Targeting tumor-associated macrophages in colon cancer: mechanisms and therapeutic strategies.
  3. The role of the tumor microenvironment and inflammatory pathways in driving drug resistance in gastric cancer: A systematic review and meta-analysis.
  4. Natural killer cells: the immune frontline against circulating tumor cells.
  5. Tumor cell-derived osteopontin promotes tumor fibrosis indirectly via tumor-associated macrophages.
  6. Targeting myeloid cells for hematological malignancies: the present and future.
  7. Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion.
  8. CXCR4/CXCL12 blockade therapy; a new horizon in TNBC therapy.
  9. Interplay between the complement system and other immune pathways in the tumor microenvironment.
  10. Flagellin engineering enhances CAR-T cell function by reshaping tumor microenvironment in solid tumors.
  11. The Role of Inflammation in Cancer: Mechanisms of Tumor Initiation, Progression, and Metastasis.
  12. Astragaloside III inhibits MAPK-mediated M2 tumor-associated macrophages to suppress the progression of lung Cancer cells via Akt/mTOR signaling pathway.
  13. APOE Drives Glioma Progression by Modulating CCL5/CCR5 Signaling in the Tumor Microenvironment and Inducing M2 Macrophage Polarization.
  14. p53: A player in the tumor microenvironment.
  15. Metabolic reprogramming in T cell senescence: a novel strategy for cancer immunotherapy.
  16. Systemic inflammation in response to radiation drives the genesis of an immunosuppressed tumor microenvironment.
  17. Bufalin inhibits immune escape in metastatic colorectal cancer by regulating M2 macrophage polarization.
  18. CRISPR-Cas9 knockout of DGKα/ζ improves the anti-tumor activities of TAG-72 CAR-T cells in ovarian cancer.
  19. Organoid models of ovarian cancer: resolving immune mechanisms of metabolic reprogramming and drug resistance.
  20. The conflicting role highlights the complexity of GSDMs in cancer.
  21. Age- and diet-instructed metabolic rewiring of the tumor-immune microenvironment.
  22. Myeloid cells in the microenvironment of brain metastases.
  23. Targeting ALPPL2 with a novel CD89 bispecific antibody reprograms macrophages to enhance anti-tumor immunity.
  24. [Research Advances in Targeting the YAP/TAZ Signaling Pathway 
to Improve Cancer Immunotherapy].
  25. The solid tumor microenvironment and related targeting strategies: a concise review.
  26. Current applications of radiomics in the assessment of tumor microenvironment of hepatocellular carcinoma.
  27. PRMT5 deficiency in myeloid cells reprograms macrophages to enhance antitumor immunity and synergizes with anti-PD-L1 therapy.
  28. Caspase-6/Gasdermin C-Mediated Tumor Cell Pyroptosis Promotes Colorectal Cancer Progression Through CXCL2-Dependent Recruitment of Myeloid-Derived Suppressor Cells.
  29. Unravelling the role of extracellular vesicles in cervical cancer: Mechanisms of progression, resistance, and emerging therapeutic strategies.
  30. The oncobiome; what, so what, now what?
  31. Pipelines for lymphocyte homeostasis maintenance during cancer immunotherapy.
  32. Neural crest-associated gene FOXD1 induces an immunosuppressive microenvironment by regulating myeloid-derived suppressor cells in melanoma.
  33. Designer DNA nanocages modulate anti-oxidative and anti-inflammatory responses in tumor associated macrophages.
  34. Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies.
  35. Targeting B4GALT3 in BMSCs-EVs for Therapeutic Control of HCC via NF-κB pathway inhibition.
  36. Increased fatty acid delivery by tumor endothelium promotes metastatic outgrowth.
  37. Targeting SCD triggers lipotoxicity of cancer cells and enhances anti-tumor immunity in breast cancer brain metastasis mouse models.
  38. Succinate-loaded tumor cell-derived microparticles reprogram tumor-associated macrophage metabolism.
  1. Front Immunol. 2025 ;16 1563303
    Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives.
    Xuan-Yu Gu, Jia-Li Yang, Rui Lai, Zheng-Jun Zhou, Dan Tang, Long Hu, Li-Jin Zhao.
      Lactate has emerged as a key regulator in the tumor microenvironment (TME), influencing both tumor progression and immune dynamics. As a byproduct of aerobic glycolysis, lactate satisfies the metabolic needs of proliferating tumor cells while reshaping the TME to facilitate immune evasion. Elevated lactate levels inhibit effector immune cells such as CD8+ T and natural killer cells, while supporting immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells, thus fostering an immunosuppressive environment. Lactate promotes epigenetic reprogramming, stabilizes hypoxia-inducible factor-1α, and activates nuclear factor kappa B, leading to further immunological dysfunction. In this review, we examined the role of lactate in metabolic reprogramming, immune suppression, and treatment resistance. We also discuss promising therapeutic strategies targeting lactate metabolism, including lactate dehydrogenase inhibitors, monocarboxylate transporter inhibitors, and TME neutralization methods, all of which can restore immune function and enhance immunotherapy outcomes. By highlighting recent advances, this review provides a theoretical foundation for integrating lactate-targeted therapies into clinical practice. We also highlight the potential synergy between these therapies and current immunotherapeutic strategies, providing new avenues for addressing TME-related challenges and improving outcomes for patients with cancer.
    Keywords:  immunosuppression; immunotherapy; lactate metabolism; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1563303
  2. Front Immunol. 2025 ;16 1573917
    Targeting tumor-associated macrophages in colon cancer: mechanisms and therapeutic strategies.
    Jianqin Xiang, Jian Wang, Huihui Xiao, Chengchen Huang, Chunrong Wu, Lin Zhang, Chenyuan Qian, Debing Xiang.
      Colon cancer (CC) remains a primary contributor to cancer-related fatalities worldwide, driven by difficulties in early diagnosis and constrained therapeutic options. Recent studies underscore the importance of the tumor microenvironment (TME), notably tumor-associated macrophages (TAMs), in fostering malignancy progression and therapy resistance. Through their inherent plasticity, TAMs facilitate immunosuppression, angiogenic processes, metastatic spread, and drug tolerance. In contrast to M1 macrophages, which promote inflammatory and tumoricidal responses, M2 macrophages support tumor expansion and dissemination by exerting immunosuppressive and pro-angiogenic influences. Consequently, manipulating TAMs has emerged as a potential avenue to enhance treatment effectiveness. This review outlines the origins, polarization states, and functions of TAMs in CC, highlights their role in driving tumor advancement, and surveys ongoing efforts to target these cells for better patient outcomes. Emerging therapeutic strategies aimed at modulating TAM functions - including depletion strategies, reprogramming approaches that shift M2-polarized TAMs toward an M1 phenotype, and inhibition of key signaling pathways sustaining TAM-mediated immunosuppression-are currently under active investigation. These approaches hold promise in overcoming TAM - induced resistance and improving immunotherapeutic efficacy in CC.
    Keywords:  M1 macrophages; chemokines; colon cancer; immune suppression; metastasis; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1573917
  3. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 07. pii: S0925-4439(25)00166-8. [Epub ahead of print]1871(6): 167821
    The role of the tumor microenvironment and inflammatory pathways in driving drug resistance in gastric cancer: A systematic review and meta-analysis.
    Francesco Albano, Francesca Lospinoso Severini, Giovanni Calice, Pietro Zoppoli, Geppino Falco, Tiziana Notarangelo.
      Tumor microenvironment (TME) plays a pivotal role in progression and low responsiveness to chemotherapy of gastric cancer (GC). The cascade of events that culminate with a sustained and chronic activation of inflammatory pathways underlies gastric tumorigenesis. Infiltrating immune cells enrolling in crosstalk with cancer cells that regulate inflammatory and immune status, generating an immunosuppressive TME that influences the response to therapy. Here we discuss the role of TME and the activation of inflammatory pathways to comprehend strategies to improve drug response. Furthermore, we provides systematic insight the role of TME cytotypes and related signatures reinforcing the critical roles of TAMs and Tregs, in promoting GC chemoresistance and tumor progression.
    Keywords:  Cytokines; Drug resistance; Gastric cancer; Immune cells; Inflammation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167821
  4. J Exp Clin Cancer Res. 2025 Apr 10. 44(1): 118
    Natural killer cells: the immune frontline against circulating tumor cells.
    Doryan Masmoudi, Martin Villalba, Catherine Alix-Panabières.
      Natural killer (NK) play a key role in controlling tumor dissemination by mediating cytotoxicity towards cancer cells without the need of education. These cells are pivotal in eliminating circulating tumor cells (CTCs) from the bloodstream, thus limiting cancer spread and metastasis. However, aggressive CTCs can evade NK cell surveillance, facilitating tumor growth at distant sites. In this review, we first discuss the biology of NK cells, focusing on their functions within the tumor microenvironment (TME), the lymphatic system, and circulation. We then examine the immune evasion mechanisms employed by cancer cells to inhibit NK cell activity, including the upregulation of inhibitory receptors. Finally, we explore the clinical implications of monitoring circulating biomarkers, such as NK cells and CTCs, for therapeutic decision-making and emphasize the need to enhance NK cell-based therapies by overcoming immune escape mechanisms.
    Keywords:  Biomarkers; Cancer; Circulating tumor cells; Liquid Biopsy; Natural killer cells
    DOI:  https://doi.org/10.1186/s13046-025-03375-x
  5. J Transl Med. 2025 Apr 11. 23(1): 432
    Tumor cell-derived osteopontin promotes tumor fibrosis indirectly via tumor-associated macrophages.
    Yuying Tan, Yong-Guang Yang, Xiaoying Zhang, Lei Zhao, Xiaocong Wang, Wentao Liu.
       BACKGROUND: High fibrosis of the tumor microenvironment (TME) not only impedes the effective infiltration of T cells but also serves as a physical barrier to inhibit the penetration of chemotherapy drugs. Triple-negative breast cancer (TNBC) is characterized by significant infiltration of tumor-associated macrophages (TAMs) and high fibrosis. However, the mechanism of high fibrosis in such tumors is still under debate.
    METHODS: We first investigated the correlation between tumor-derived osteopontin (OPN) and tumor fibrosis as well as TAM enrichment using a tumor model characterized by OPN genetic inactivation or overexpression. We further compared the effects of macrophage depletion on tumor fibrosis in mice bearing TNBC tumors (4T1WT or 4T1Spp1 - KO). To elucidate the mechanism by which TAMs promote tumor fibrosis, we evaluated their potential to recruit cancer-associated fibroblasts (CAFs) through in vitro migration assays and compared the production of transforming growth factor-beta 1 (TGFβ1) among different TAM subpopulations.
    RESULTS: Our study revealed that OPN secretion by tumor cells correlates positively with both tumor fibrosis and TAM enrichment. Specifically, within the enriched TAM population, Ly6C+CD206- TAMs recruit CAFs via CCL5 secretion, while Ly6C-CD206high TAMs secrete TGFβ1 to activate CAFs. Blocking the tumor cell-derived OPN can effectively prevent tumor fibrosis.
    CONCLUSIONS: This study shows that tumor-derived OPN primarily drives TAM enrichment in mouse cancer model, indirectly promoting tumor fibrosis through Ly6C+CD206-/low and Ly6C-CD206high TAMs. Our findings have potential application in preventing tumors from excessive fibrosis and enhancing the efficacy of immunotherapy and chemotherapy.
    Keywords:  Cancer-associated fibroblast; Fibrosis; Osteopontin; Tumor microenvironment; Tumor-associated macrophage
    DOI:  https://doi.org/10.1186/s12967-025-06444-z
  6. Biomark Res. 2025 Apr 10. 13(1): 59
    Targeting myeloid cells for hematological malignancies: the present and future.
    Zihui Guan, Zhengqi Zhang, Kaiyan Wang, Shukai Qiao, Teng Ma, Lina Wu.
      Hematological malignancies are a diverse group of cancers that originate in the blood and bone marrow and are characterized by the abnormal proliferation and differentiation of hematopoietic cells. Myeloid blasts, which are derived from normal myeloid progenitors, play a central role in these diseases by disrupting hematopoiesis and driving disease progression. In addition, other myeloid cells, including tumor-associated macrophages and myeloid-derived suppressor cells, adapt dynamically to the tumor microenvironment, where they can promote immune evasion and resistance to treatment. This review explores the unique characteristics and pathogenic mechanisms of myeloid blasts, the immunosuppressive roles of myeloid cells, and their complex interactions within the TME. Furthermore, we highlight emerging therapeutic approaches targeting myeloid cells, focusing on strategies to reprogram their functions, inhibit their suppressive effects, or eliminate pathological populations altogether, as well as the latest preclinical and clinical trials advancing these approaches. By integrating insights from these studies, we aim to provide a comprehensive understanding of the roles of myeloid cells in hematological malignancies and their potential as therapeutic targets.
    Keywords:  Hematological malignancies; Immune checkpoint; Myeloid cells; Targeted therapy; Targeting myeloid cells
    DOI:  https://doi.org/10.1186/s40364-025-00775-1
  7. Cancer Cell. 2025 Apr 01. pii: S1535-6108(25)00116-3. [Epub ahead of print]
    Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion.
    Yinghua Zhu, Ziwei Zhou, Xin Du, Xiaorong Lin, Zhi-Mei Liang, Si Chen, Yiwei Sun, Yue Wang, Zhenkun Na, Zhiyong Wu, Jiaxin Zhong, Beinan Han, Xiangping Zhu, Wenkui Fu, Hongde Li, Man-Li Luo, Hai Hu.
      Arginine metabolism reshapes the tumor microenvironment (TME) into a pro-tumor niche through complex metabolic cross-feeding among various cell types. However, the key intercellular metabolic communication that mediates the collective effects of arginine metabolism within the TME remains unclear. Here, we reveal that the metabolic interplay between cancer cells and macrophages plays a dominant role in arginine-driven breast cancer progression. Within the TME, breast cancer cells serve as the primary source of arginine, which induces a pro-tumor polarization of tumor-associated macrophages (TAMs), thereby suppressing the anti-tumor activity of CD8+ T cells. Notably, this cancer cell-macrophage interaction overrides the arginine-mediated enhancement of CD8+ T cell anti-tumor activity. Mechanistically, polyamines derived from arginine metabolism enhance pro-tumor TAM polarization via thymine DNA glycosylase (TDG)-mediated DNA demethylation, regulated by p53 signaling. Importantly, targeting the arginine-polyamine-TDG axis between cancer cells and macrophages significantly suppresses breast cancer growth, highlighting its therapeutic potential.
    Keywords:  arginine; breast cancer; metabolic communication; polyamine; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.ccell.2025.03.015
  8. Med Oncol. 2025 Apr 11. 42(5): 161
    CXCR4/CXCL12 blockade therapy; a new horizon in TNBC therapy.
    Abdulrahman Qais Khaleel, Farag M A Altalbawy, Majid S Jabir, Thikra F Hasan, Vicky Jain, Vikrant Abbot, Prashant Nakash, M Ravi Kumar, Yasser Fakri Mustafa, Mohammed Abed Jawad.
      The only subtype of breast cancer (BC) without specific therapy is triple-negative breast cancer (TNBC), which represents 15-20% of incidence cases of BC. TNBC encompasses transformed and nonmalignant cells, including cancer-associated fibroblasts (CAF), endothelial vasculature, and tumor-infiltrating cells. These nonmalignant cells, soluble factors (e.g., cytokines), and the extracellular matrix (ECM) form the tumor microenvironment (TME). The TME is made up of these nonmalignant cells, ECM, and soluble components, including cytokines. Direct cell-to-cell contact and soluble substances like cytokines (e.g., chemokines) may facilitate interaction between cancer cells and the surrounding TME. Through growth-promoting cytokines, TME not only enables the development of cancer but also confers therapy resistance. New treatment targets will probably be suggested by comprehending the processes behind tumor development and progression as well as the functions of chemokines in TNBC. In this light, several investigations have shown the pivotal function of the C-X-C motif chemokine ligand 12 (CXCL12 or SDF-1) axis and chemokine receptor type 4 (CXCR4) in the pathophysiology of TNBC. This review provides an overview of the CXCR4/CXCL12 axis' function in TNBC development, metastasis, angiogenesis, and treatment resistance. A synopsis of current literature on targeting the CXCR4/CXCL12 axis for treating and managing TNBC has also been provided.
    Keywords:  CXCL12; CXCR4; Drug resistance; Growth; Metastasis; TNBC
    DOI:  https://doi.org/10.1007/s12032-025-02705-5
  9. Semin Immunol. 2025 Apr 09. pii: S1044-5323(25)00023-5. [Epub ahead of print]78 101951
    Interplay between the complement system and other immune pathways in the tumor microenvironment.
    Cecilia Garlanda, Monica Dambra, Elena Magrini.
      Tumor growth and spread are sustained by the tumor microenvironment. Inflammatory cells and pathways have a fundamental role in the tumor microenvironment, driving or conditioning the functional activation of other leukocyte subsets and favoring evasion of anti-tumor immunity. One of the inflammatory pathways contributing to cancer-related inflammation is the complement system. Complement has long been considered an immune mechanism associated with immunosurveillance. More recently it emerged as a tumor promoting pathway, due to direct effects on cancer cells or indirect effects via immunosuppression driven by myeloid cells. The role of complement in cancer is complex and ambiguous, and depends on the tumor type and stage, as well as other factors including oncogenic drivers, leukocyte infiltration, interactions with other tumor microenvironment components or tumor cells. Other factors of complexity include the source of complement molecules, its canonical or non-canonical extracellular functions, its potential intracellular activation, and the interaction with other systems, such as the coagulation or the microbiome. Preclinical studies generally demonstrate the involvement of complement activation in smouldering inflammation in cancer and promotion of an immunosuppressive environment. These studies paved the way for clinical trials aimed at enhancing the potential of immunotherapy, in particular by targeting complement-dependent myeloid-sustained immunosuppression. However, the complex role of complement in cancer and the multiplicity of complement players may represent stumbling blocks and account for failures of clinical trials, and suggest that further studies are required to identify patient subsets who may benefit from specific complement molecule targeting in combination with conventional therapies or immunotherapy. Here, we will discuss the anti- or pro-tumor role of complement activation in cancer, focusing on the interactions of complement with immune cells within the tumor microenvironment, in particular the myeloid compartment. Furthermore, we will examine the potential of complement targeting in cancer treatment, particularly in the context of macrophage reprogramming.
    Keywords:  Cancer-related inflammation; Complement; Macrophages; Myeloid cells; Tumor-associated; Tumor-associated neutrophils
    DOI:  https://doi.org/10.1016/j.smim.2025.101951
  10. J Immunother Cancer. 2025 Apr 05. pii: e010237. [Epub ahead of print]13(4):
    Flagellin engineering enhances CAR-T cell function by reshaping tumor microenvironment in solid tumors.
    Xiangyun Niu, Pengchao Zhang, Liujiang Dai, Xixia Peng, Zhongming Liu, Yexiao Tang, Guizhong Zhang, Xiaochun Wan.
       BACKGROUND: Adoptive cell therapy using genetically engineered chimeric antigen receptor (CAR)-T cells is a new type of immunotherapy that directs T cells to target cancer specifically. Although CAR-T therapy has achieved significant clinical efficacy in treating hematologic malignancies, its therapeutic benefit in solid tumors is impeded by the immunosuppressive tumor microenvironment (TME). Therefore, we sought to remodel the TME by activating tumor-infiltrating immune cells to enhance the antitumor function of CAR-T cells.
    METHODS: We engineered CAR-T cells expressing Salmonella flagellin (Fla), a ligand for toll-like receptor 5, to activate immune cells and reshape the TME in solid tumors. Functional validation of the novel Fla-engineered CAR-T cells was performed in co-cultures and mouse tumor models.
    RESULTS: Fla could activate tumor-associated macrophages and dendritic cells, reshaping the TME to establish an "immune-hot" milieu. Notably, this "cold" to "hot" evolution not only improved CAR-T cell function for better control of target-positive tumors, but also encouraged the production of endogenous cytotoxic CD8+T cells, which targeted more tumor-associated antigens and were thus more effective against tumors with antigenic heterogeneity.
    CONCLUSION: Our study reveals the potential and cellular mechanisms for Fla to rewire antitumor immunity. It also implies that modifying CAR-T cells to express Fla is a viable strategy to improve the efficacy of CAR-T cell treatment against solid tumors.
    Keywords:  Chimeric antigen receptor - CAR; Immunotherapy; Solid tumor; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2024-010237
  11. Cells. 2025 Mar 25. pii: 488. [Epub ahead of print]14(7):
    The Role of Inflammation in Cancer: Mechanisms of Tumor Initiation, Progression, and Metastasis.
    Atsushi Nishida, Akira Andoh.
      Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion and metastasis. Tumors often create an inflammatory microenvironment that induces angiogenesis, immune suppression, and malignant growth. Immune cells within the tumor microenvironment interact actively with cancer cells, which drives progression through complex molecular mechanisms. Chronic inflammation is triggered by factors such as infections, obesity, and environmental toxins and is strongly linked to increased cancer risk. However, acute inflammatory responses can sometimes boost antitumor immunity; thus, inflammation presents both challenges and opportunities for therapeutic intervention. This review examines how inflammation contributes to tumor biology, emphasizing its dual role as a critical factor in tumorigenesis and as a potential therapeutic target.
    Keywords:  cancer; chronic inflammation; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells14070488
  12. Int Immunopharmacol. 2025 Apr 03. pii: S1567-5769(25)00536-3. [Epub ahead of print]154 114546
    Astragaloside III inhibits MAPK-mediated M2 tumor-associated macrophages to suppress the progression of lung Cancer cells via Akt/mTOR signaling pathway.
    Yan Sun, Jia-Qi Liu, Wen-Jing Chen, Wei-Feng Tang, Yao-Long Zhou, Bao-Jun Liu, Ying Wei, Jing-Cheng Dong.
      Tumor-associated macrophages (TAMs) play a key role in facilitating a range of cancerous processes by modulating the tumor microenvironment thus being a target for cancer treatment. Astragaloside III (AS-III), a compound derived from Astragalus triterpenoid saponins, has demonstrated immunomodulatory and anticancer properties, but the underlying mechanism remains unclear. Here, we demonstrated that AS-III suppressed metastasis, angiogenesis and induced apoptosis of lung cancer in vitro and in vivo by inhibiting macrophage M2 polarization and inducing M1 phenotype transformation. This was achieved through the inhibition of the MAPK signaling pathway. Furthermore, the tumor inhibitory effects of AS-III were found to be mediated by the Akt/mTOR pathway. Overall, these results highlight the role of AS-III in modifying the TAMs in TME, offering fresh perspectives on tumor immunotherapy by means of targeting macrophage.
    Keywords:  Astragaloside III; Lung cancer; Macrophage polarization; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.intimp.2025.114546
  13. Immunobiology. 2025 Mar 22. pii: S0171-2985(25)00029-4. [Epub ahead of print]230(3): 152895
    APOE Drives Glioma Progression by Modulating CCL5/CCR5 Signaling in the Tumor Microenvironment and Inducing M2 Macrophage Polarization.
    Wei Huang, Weimin Li, Xingyu Chen, Chengwei Xiang, Ke Luo.
       BACKGROUND: Tumor-associated macrophages (TAMs) are pivotal in shaping the tumor microenvironment (TME) during cancer progression. Emerging evidence indicates that dysregulation of key signaling pathways in cancer cells drives the secretion of various cytokines, modulating TAMs function. This study aimed to explore how glioblastoma cells regulate macrophages and establish a TME conducive to tumor immune escape.
    METHODS: In previous bioinformatics studies, we identified abnormally expressed genes in glioblastoma patients. Among them, the metabolism-related protein APOE garnered particular attention. We generated U87 and U251 cell lines with altered APOE expression to evaluate cancer cell invasion, migration, and inflammatory cytokine secretion through scratch assays, Transwell assays, and ELISA, respectively. Additionally, we established a co-culture system of cancer cells and monocytes THP-1 to assess the impact of shAPOE tumor cells on macrophage polarization using flow cytometry, Western blot, and immunofluorescence techniques.
    RESULT: Knockdown of APOE significantly reduced the viability, invasion, and migration capabilities of U87 and U251 cells. ELISA results also showed that APOE knockdown cells secreted higher levels of IL-6, IL-12, and TNF-α, while CCL5 and TGF-β secretion was markedly reduced. In macrophage studies, we observed that APOE knockdown altered the M1/M2 polarization ratio in THP-1 monocytes, with CCR5 inhibition further decreasing M2 macrophage proportions. Immunofluorescence analysis revealed that the reduction of M2 macrophages was dependent on APOE and CCL5.
    CONCLUSION: Our findings indicate that APOE knockdown suppresses glioblastoma cell migration, invasion, and CCL5 secretion, while enhancing the production of tumor-suppressive cytokines.
    Keywords:  APOE; CCL5-CCR5 signaling pathway; Glioblastoma; Immunosuppressive Mechanisms; Immunotherapy; Tumor microenvironment; Tumor-associated Macrophages
    DOI:  https://doi.org/10.1016/j.imbio.2025.152895
  14. Oncol Res. 2025 ;33(4): 795-810
    p53: A player in the tumor microenvironment.
    Shuang Zhao, Hongyong Wen, Baiqi Wang, Qinglin Xiong, Lanxin Li, Ailan Cheng.
      Approximately half of all cancers have p53 inactivating mutations, in addition to which most malignancies inactivate the p53 pathway by increasing p53 inhibitors, decreasing p53 activators, or inactivating p53 downstream targets. A growing number of researches have demonstrated that p53 can influence tumor progression through the tumor microenvironment (TME). TME is involved in the process of tumor development and metastasis and affects the clinical prognosis of patients. p53 participates in host immunity and engages in the immune landscape of the TME, but the specific mechanisms remain to be investigated. This review briefly explores the interactions between different states of p53 and TME components and their mechanisms, as well as their effects on tumor progression. To understand the progress of drug development and clinical studies related to p53 and tumor microenvironment.
    Keywords:  Cancer therapy; Mutant p53; Tumor microenvironment (TME); Wild type p53; p53
    DOI:  https://doi.org/10.32604/or.2025.057317
  15. Cell Death Discov. 2025 Apr 09. 11(1): 161
    Metabolic reprogramming in T cell senescence: a novel strategy for cancer immunotherapy.
    Li Liu, Zhanying Hao, Xi Yang, Yan Li, Siyang Wang, Linze Li.
      The complex interplay between cancer progression and immune senescence is critically influenced by metabolic reprogramming in T cells. As T cells age, especially within the tumor microenvironment, they undergo significant metabolic shifts that may hinder their proliferation and functionality. This manuscript reviews how metabolic alterations contribute to T cell senescence in cancer and discusses potential therapeutic strategies aimed at reversing these metabolic changes. We explore interventions such as mitochondrial enhancement, glycolytic inhibition, and lipid metabolism adjustments that could rejuvenate senescent T cells, potentially restoring their efficacy in tumor suppression. This review also focuses on the significance of metabolic interventions in T cells with aging and further explores the future direction of the metabolism-based cancer immunotherapy in senescent T cells.
    DOI:  https://doi.org/10.1038/s41420-025-02468-y
  16. Neoplasia. 2025 Apr 03. pii: S1476-5586(25)00043-0. [Epub ahead of print]64 101164
    Systemic inflammation in response to radiation drives the genesis of an immunosuppressed tumor microenvironment.
    Lin Ma, Jian-Hua Mao, Mary Helen Barcellos-Hoff.
      The composition of the tumor immune microenvironment has become a major determinant of response to therapy, particularly immunotherapy. Clinically, a tumor microenvironment lacking lymphocytes, so-called "cold" tumors, are considered poor candidates for immune checkpoint inhibition. In this review, we describe the diversity of the tumor immune microenvironment in breast cancer and how radiation exposure alters carcinogenesis. We review the development and use of a radiation-genetic mammary chimera model to clarify the mechanism by which radiation acts. Using the chimera model, we demonstrate that systemic inflammation elicited by a low dose of radiation is key to the construction of an immunosuppressive tumor microenvironment, resulting in aggressive, rapidly growing tumors lacking lymphocytes. Our experimental studies inform the non-mutagenic mechanisms by which radiation affects cancer and provide insight into the genesis of cold tumors.
    Keywords:  DNA damage response; Evolution; Immunophenotype; Radiation carcinogenesis; TGFβ; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.neo.2025.101164
  17. Apoptosis. 2025 Apr 05.
    Bufalin inhibits immune escape in metastatic colorectal cancer by regulating M2 macrophage polarization.
    Chang Lu, Jing Shang, Manli Xie, Yuan Zhu, Jiani Zhong, Yujie He, Zengyou Xiao, Wen Chen, Ze-An Yang, Xiaoxia Tang, Peihao Yin, Jinbao Chen.
      The prognosis for patients with metastatic colorectal cancer (mCRC) remains poor primarily owing to immune escape caused by immunosuppressive tumor microenvironment (TME). M2 tumor-associated macrophages (TAMs) have been considered as a pivotal role in sustaining the immunosuppressive character in TME. Our previous studies have found that highly mCRC cells could promote M2 TAMs polarization, leading to the exhaustion of T cell antitumor immunity. Studies have reported that Bufalin (BU) could reverse the immunosuppressive TME via regulating TAMs polarization, but the mechanisms underlying remain elusive. In this study, we demonstrated that KLF4 secreted by highly mCRC cells not only promoted the polarization to M2 TAMs but also up-regulated the PD-L1 expression in TAMs, leading to suppressing cytotoxic T lymphocyte (CTL) function to facilitate tumor immune escape. Mechanistically, BU targeted the SRC-3 protein to reduce KLF4 release in highly mCRC cells to regulate the polarization of M2 TAMs and down-regulate PD-L1 expression in TAMs, resulting in reprogramming of the TME and enhancing the anti-tumor immunity. These results have also been validated in both subcutaneous tumor models and orthotopic tumor models. Overall, this research further elucidates the anti-tumor mechanism of BU for inhibiting immune escape in mCRC and facilitate exploitation of a new potential macrophage-based mCRC immunotherapeutic modality.
    Keywords:  Bufalin; Immune escape; Krüppel-like factor 4; Metastatic colorectal cancer; Tumor-associated macrophage
    DOI:  https://doi.org/10.1007/s10495-025-02107-y
  18. Mol Ther Oncol. 2025 Jun 18. 33(2): 200962
    CRISPR-Cas9 knockout of DGKα/ζ improves the anti-tumor activities of TAG-72 CAR-T cells in ovarian cancer.
    Vera J Evtimov, Nhu-Y N Nguyen, Maree V Hammett, Aleta Pupovac, Peter J Hudson, Junli Zhuang, Jae Young Lee, Seokjoong Kim, Alan O Trounson, Richard L Boyd, Runzhe Shu.
      High recurrence and chemoresistance in solid tumors, like ovarian cancer, stress the need for new therapies. Chimeric antigen receptor (CAR)-T cells show promise but face challenges due to tumor heterogeneity and immune suppression in the tumor microenvironment (TME). Thus, novel approaches are needed to further enhance the efficacy of CAR-T cell therapies. In T cell therapies, inhibiting checkpoint molecules is crucial for overcoming exhaustion and boosting anti-tumor activity. Additionally, prioritizing safety by engineering cells to target markers absent on normal healthy cells reduces off-target risks. We targeted tumor-associated glycoprotein 72 (TAG-72), an oncofetal antigen highly expressed in adenocarcinomas like ovarian cancer, by engineering TAG-72 CAR-T cells and used CRISPR-Cas9 to knock out the T cell-inhibitory enzymes diacylglycerol kinase (DGK) α and ζ. DGKα/ζ knockout (KO) did not impact CAR-T cell viability or phenotype. These cells selectively killed TAG-72-expressing cancer cells in vitro and ablated established tumors in vivo for up to 100 days, whereas non-deleted control TAG-72 CAR-T cells showed tumor relapse around 40 days. These findings highlight the potential of CRISPR-induced DGKα/ζ KO to enhance CAR-T cell efficacy against solid tumors such as ovarian cancer, offering a promising avenue for improved cancer therapies.
    Keywords:  CAR-T cells; CRISPR-Cas9; DGK; MT: Regular Issue; TAG-72; ovarian cancer
    DOI:  https://doi.org/10.1016/j.omton.2025.200962
  19. Front Immunol. 2025 ;16 1573686
    Organoid models of ovarian cancer: resolving immune mechanisms of metabolic reprogramming and drug resistance.
    Lanyue Zhang, Jiangnan Zhao, Chunyu Su, Jianxi Wu, Lai Jiang, Hao Chi, Qin Wang.
      Metabolic reprogramming is a hallmark of ovarian cancer, enabling tumor progression, immune evasion and drug resistance. The tumor microenvironment (TME) further shapes metabolic adaptations, enabling cancer cells to withstand hypoxia and nutrient deprivation. While organoid models provide a physiologically relevant platform for studying these processes, they still lack immune and vascular components, limiting their ability to fully recapitulate tumor metabolism and drug responses. In this study, we investigated the key metabolic mechanisms involved in ovarian cancer progression, focusing on glycolysis, lipid metabolism and amino acid metabolism. We integrated metabolomic analyses and drug sensitivity assays to explore metabolic-TME interactions using patient-derived, adult stem cell-derived and iPSC-derived organ tissues. Among these, we found that glycolysis, lipid metabolism and amino acid metabolism play a central role in tumor progression and chemotherapy resistance. We identified methylglyoxal (MGO)-mediated BRCA2 dysfunction as a driver of immune escape, a role for sphingolipid signaling in tumor proliferation and a role for kynurenine metabolism in CD8+ T cell suppression. In addition, PI3K/AKT/mTOR and Wnt/β-catenin pathways promote chemoresistance through metabolic adaptation. By elucidating the link between metabolic reprogramming and immune evasion, this study identifies key metabolic vulnerabilities and potential drug targets in ovarian cancer. Our findings support the development of metabolically targeted therapies and increase the utility of organoid-based precision medicine models.
    Keywords:  drug resistance; immune escape; metabolic reprogramming; molecular mechanisms; organoid; ovarian cancer; personalized therapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1573686
  20. Front Immunol. 2025 ;16 1531695
    The conflicting role highlights the complexity of GSDMs in cancer.
    Sijia He, Qian Huang, Jin Cheng.
      Gasdermins (GSDMs) are an important family of proteins that have received extensive attention in tumor research in recent years. They directly induce tumor cell death by mediating pyroptosis and also regulate the recognition and clearance of tumor cells by the immune system by affecting the microenvironment. Therefore, it is of great significance to investigate the role of GSDMs in tumor development and tumor microenvironment. It can not only reveal new mechanisms of cancer development, but also provide theoretical basis for the development of novel anti-tumor therapeutic strategies. This literature review aims to systematically summarize the dual roles of GSDMs in tumor development and their interactions with the tumor microenvironment, and to focus on the importance of GSDM-mediated pyroptosis in anti-cancer therapy, with a view to providing guidance for future research directions.
    Keywords:  anti-cancer therapy; cancer; gasdermins; pyroptosis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1531695
  21. J Exp Med. 2025 Jun 02. pii: e20241102. [Epub ahead of print]222(6):
    Age- and diet-instructed metabolic rewiring of the tumor-immune microenvironment.
    Ana Belén Plata-Gómez, Ping-Chih Ho.
      The tumor-immune microenvironment (TIME) plays a critical role in tumor development and metastasis, as it influences the evolution of tumor cells and fosters an immunosuppressive state by intervening the metabolic reprogramming of infiltrating immune cells. Aging and diet significantly impact the metabolic reprogramming of the TIME, contributing to cancer progression and immune evasion. With aging, immune cell function declines, leading to a proinflammatory state and metabolic alterations such as increased oxidative stress and mitochondrial dysfunction, which compromise antitumor immunity. Similarly, dietary factors, particularly high-fat and high-sugar diets, promote metabolic shifts, creating a permissive TIME by fostering tumor-supportive immune cell phenotypes while impairing the tumoricidal activity of immune cells. In contrast, dietary restrictions have been shown to restore immune function by modulating metabolism and enhancing antitumor immune responses. Here, we discuss the intricate interplay between aging, diet, and metabolic reprogramming in shaping the TIME, with a particular focus on T cells, and highlight therapeutic strategies targeting these pathways to empower antitumor immunity.
    DOI:  https://doi.org/10.1084/jem.20241102
  22. Biochim Biophys Acta Rev Cancer. 2025 Apr 04. pii: S0304-419X(25)00053-8. [Epub ahead of print] 189311
    Myeloid cells in the microenvironment of brain metastases.
    Nian Chen, Tao Zhang, Xianyan Yang, Di Wang, Shicang Yu.
      Brain metastasis (BrM) from peripheral solid tumors has a high mortality rate and remains a daunting clinical challenge. In addition to the targeting of tumor cells, studies have focused on the regulation of the tumor microenvironment (TME) for BrM treatment. Here, through a review of recent studies, we revealed that myeloid infiltration is a common feature of the TME in BrMs from different primary sites even though the brain is regarded as an immune-privileged site and is always in an immunosuppressive state. Tumor-educated bone marrow progenitors, especially mesenchymal stem cells (MSCs), may impact the brain tropism and and phenotypic switching of myeloid cells. Additionally, chronic inflammation may be key factors regulating the immunosuppressive TME and myeloid cell reprogramming. Here, the role of myeloid cells in the formation of the TME and strategies for targeting these cells before and after BrM are reviewed, emphasizing the potential for the use of myeloid cells in BrM treatment. However, the direct relationship between the neuronal system and myeloid cell filtration is still unclear and worthy of further study.
    Keywords:  Brain metastases; Immunosuppressive; Myeloid cells; Targeting strategies; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189311
  23. Biochem Biophys Res Commun. 2025 Apr 07. pii: S0006-291X(25)00475-9. [Epub ahead of print]762 151761
    Targeting ALPPL2 with a novel CD89 bispecific antibody reprograms macrophages to enhance anti-tumor immunity.
    Lijun Xu, Bowen Yang, Junhan Zhang, Shujian Liu, Qi Zhang, Longchao Ran, Bingyu Li.
      Immunotherapy holds promise for cancer treatment, but its efficacy in solid tumors is often limited by the immunosuppressive tumor microenvironment (TME). Macrophages, abundant within the TME, can be reprogrammed to elicit anti-tumor immunity. We developed a novel bispecific antibody, ALPPL2-CD89, to specifically target and activate macrophages within the tumor. The ALPPL2-CD89 bispecific antibody demonstrated high binding affinity to both targets and significantly enhanced macrophage-mediated phagocytosis of tumor cells. In vivo studies using human CD89 transgenic mice bearing ALPPL2-expressing tumors showed significant tumor growth inhibition. Analysis of the tumor microenvironment revealed that ALPPL2-CD89 treatment increased CD3+ and CD8+ T cell infiltration, and shifted tumor-associated macrophages toward a pro-inflammatory M1 phenotype. Our findings establish ALPPL2-CD89 as a promising therapeutic candidate that effectively reprograms the myeloid compartment to drive potent anti-tumor immunity against ALPPL2-positive malignancies.
    Keywords:  ALPPL2; Bispecific antibody; CD89; Cancer immunotherapy; Macrophages
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151761
  24. Zhongguo Fei Ai Za Zhi. 2025 Mar 20. 28(3): 221-229
    [Research Advances in Targeting the YAP/TAZ Signaling Pathway 
to Improve Cancer Immunotherapy].
    Pingxu Zhang, Yiyi Zhan.
      Despite the groundbreaking advances in cancer immunotherapy achieved by immune checkpoint inhibitors (ICIs), their efficacy remains limited by the immunosuppressive tumor microenvironment (TME). Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), key effectors of the Hippo signaling pathway, play pivotal roles in tumor immune evasion. They directly regulate the expression of immune checkpoints, mediate the formation of an immunosuppressive microenvironment, inhibit T cell function, and interact with other signaling pathways to promote immune escape. Diverse strategies targeting YAP/TAZ have been developed, including direct inhibition, modulation of upstream regulators, and suppression of downstream target genes. Preclinical studies have demonstrated that combining YAP/TAZ inhibition with ICIs significantly enhances therapeutic efficacy across various tumor models. This review summarizes recent advances in understanding the role of YAP/TAZ in immune evasion within the TME and explores the potential of targeting this pathway to improve immunotherapy outcomes. Furthermore, it discusses the translational value of combination therapies based on YAP/TAZ inhibition, providing a theoretical framework and practical guidance for the development of innovative immunotherapeutic strategies and precision medicine approaches.
.
    Keywords:  Immune evasion; Immunotherapy; TAZ; Tumor microenvironment; YAP
    DOI:  https://doi.org/10.3779/j.issn.1009-3419.2025.102.08
  25. Front Immunol. 2025 ;16 1563858
    The solid tumor microenvironment and related targeting strategies: a concise review.
    Yingliang Wang, Huimin Zhou, Shuguang Ju, Xiangjun Dong, Chuansheng Zheng.
      The malignant tumor is a serious disease threatening human life. Increasing studies have confirmed that the tumor microenvironment (TME) is composed of a variety of complex components that precisely regulate the interaction of tumor cells with other components, allowing tumor cells to continue to proliferate, resist apoptosis, evade immune surveillance and clearance, and metastasis. However, the characteristics of each component and their interrelationships remain to be deeply understood. To target TME, it is necessary to deeply understand the role of various components of TME in tumor growth and search for potential therapeutic targets. Herein, we innovatively classify the TME into physical microenvironment (such as oxygen, pH, etc.), mechanical microenvironment (such as extracellular matrix, blood vessels, etc.), metabolic microenvironment (such as glucose, lipids, etc.), inflammatory microenvironment and immune microenvironment. We introduce a concise but comprehensive classification of the TME; depict the characteristics of each component in TME; summarize the existing methods for detecting each component in TME; highlight the current strategies and potential therapeutic targets for TME; discuss current challenges in presenting TME and its clinical applications; and provide our prospect on the future research direction and clinical benefits of TME.
    Keywords:  characteristic; classification; perspective; targeting strategies; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1563858
  26. Abdom Radiol (NY). 2025 Apr 10.
    Current applications of radiomics in the assessment of tumor microenvironment of hepatocellular carcinoma.
    Junghwa Choi, Andrew Gordon, Aydin Eresen, Zhuoli Zhang, Amir Borhani, Ulas Bagci, Robert Lewandowski, Dong-Hyun Kim.
      The tumor microenvironment (TME) of hepatocellular carcinoma (HCC) has garnered significant attention, especially with the rise of immunotherapy as a treatment strategy. Radiomics, an innovative technique, offers valuable insights into the intricate structure of the TME. This review highlights recent advancements in radiomics for analyzing the HCC TME, identifies key areas that warrant further research, and explores comprehensive multi-omics approaches that extend the potential of radiomics to new frontiers.
    Keywords:  Cancer therapy; Hepatocellular carcinoma; Immunotherapy; Radiomics; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00261-025-04916-w
  27. J Immunother Cancer. 2025 Apr 05. pii: e011299. [Epub ahead of print]13(4):
    PRMT5 deficiency in myeloid cells reprograms macrophages to enhance antitumor immunity and synergizes with anti-PD-L1 therapy.
    Shiyu Chen, Zheyi Chen, Bingqian Zhou, Yongyu Chen, Yiren Huang, Jian Cao, Lisong Shen, Yingxia Zheng.
       BACKGROUND: Arginine methyltransferase protein arginine methyltransferase 5 (PRMT5) plays a significant role in immune regulation, particularly within the tumor microenvironment (TME). Macrophages are crucial modulators of both innate and adaptive immune responses, and their differentiation into tumor-associated macrophages is critical in shaping the TME. Despite ongoing clinical trials of small molecule inhibitors of PRMT5 for cancer therapy, their effects on macrophages, a key component of the immune system, remain poorly understood.
    METHODS: A pan-cancer single-cell transcriptional analysis was initially conducted to investigate the expression of PRMT5 in tumor-infiltrating myeloid cells. Myeloid-specific deletion of Prmt5 in mice, as well as the use of a PRMT5-specific inhibitor, was performed to evaluate the impact of PRMT5 on macrophage polarization and tumor progression. Bulk and single-cell transcriptomics were employed to explore the mechanistic roles of PRMT5 in regulating lipid metabolism and macrophage polarization. Additionally, the therapeutic potential of combining Prmt5 deletion with anti-programmed death-ligand 1 (PD-L1) therapy was assessed to study its effects on antitumor immunity in vivo.
    RESULTS: The pan-cancer single-cell transcriptional analysis revealed that PRMT5 is highly expressed in the PPARG-macrophage subset, which correlates with poor patient survival. Myeloid-specific deletion of Prmt5 reprogrammed macrophages towards an antitumor phenotype, effectively inhibiting tumor progression. Mechanistically, PRMT5 was found to regulate lipid metabolism and drive macrophage polarization toward an anti-inflammatory state via the STAT6-PPARγ pathway, fostering an immunosuppressive TME conducive to tumor growth. Notably, Prmt5 deletion induced PD-L1 expression on myeloid cells. Combining Prmt5 deletion with anti-PD-L1 therapy significantly enhanced antitumor efficacy, demonstrating a synergistic therapeutic effect.
    CONCLUSIONS: These findings uncover a crucial role for PRMT5 in macrophage biology and suggest that targeting PRMT5 in myeloid cells offers a promising new approach for cancer immunotherapy. The combination of PRMT5 inhibition with anti-PD-L1 therapy may provide a potent strategy to reprogram the TME and enhance antitumor immune responses.
    Keywords:  Immune modulatory; Immunosuppression; Immunotherapy; Macrophage; Tumor Microenvironment
    DOI:  https://doi.org/10.1136/jitc-2024-011299
  28. Adv Sci (Weinh). 2025 Apr 11. e2411375
    Caspase-6/Gasdermin C-Mediated Tumor Cell Pyroptosis Promotes Colorectal Cancer Progression Through CXCL2-Dependent Recruitment of Myeloid-Derived Suppressor Cells.
    Hanchao Gao, Yikun Yao, Weilong Li, Zigan Xu, Wenjun Hu, Kewang Luo, Peishan Chen, Wanjing Shang, Shaodong Luan, Guojun Shi, Mengtao Cao, Pengfei Chen.
      Gasdermin (GSDM) family proteins mediate inflammatory cell pyroptosis and exert critical contributions to the pathogenesis of gastrointestinal cancers, infections, and gut mucosal inflammation. Gasdermin C (GSDMC) is overexpressed in human colorectal cancer (CRC); however, the molecular mechanisms underlying GSDMC regulation of CRC tumorigenesis are largely elusive. Here, it is found that both GSDMC expression and activation are significantly elevated in human and mouse CRC tissues. Gsdmc2/3/4 deficiency attenuates tumor progression in both chemically induced CRC mouse model and spontaneous intestinal tumor model. Mechanistically, under hypoxia and low-glucose condition, GSDMC2/3/4 are directly activated by Caspase-6, but not by Caspase-8, as previously reported in other cancers. GSDMC2/3/4-mediated pyroptosis in tumor cells leads to the release of high mobility group protein B1 (HMGB1), which enhances the expression of chemokine attractant C-X-C motif chemokine 2 (CXCL2) in surrounding tumor cells. Subsequently, the elevated CXCL2 secretion from tumor cells promotes the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment (TME) through C-X-C chemokine receptor type 2 (CXCR2), thereby facilitating CRC progression. These findings reveal a mechanism by which Caspase-6/GSDMC-mediated tumor cell pyroptosis, in response to hypoxic and low-glucose conditions, remodels the immunosuppressive microenvironment through CXCL2-dependent recruitment of MDSCs. These results identify GSDMC as a potential drug target for CRC therapy.
    Keywords:  CXCL2; GSDMC; HMGB1; colorectal cancer; myeloid‐derived suppressor cells
    DOI:  https://doi.org/10.1002/advs.202411375
  29. Gene. 2025 Apr 07. pii: S0378-1119(25)00255-0. [Epub ahead of print] 149467
    Unravelling the role of extracellular vesicles in cervical cancer: Mechanisms of progression, resistance, and emerging therapeutic strategies.
    Michelle van der Merwe, Kathy Myburgh, Cathie Garnis, Rebecca Towle, Anna-Mart Engelbrecht.
      Cervical cancer remains a significant global health challenge, particularly in its advanced stages, where treatment resistance complicates effective management. Extracellular vesicles (EVs) are crucial mediators of tumor progression and resistance, primarily through the transfer of miRNA cargo. In cervical cancer, specific miRNAs, including oncogenic miRNAs such as miR-21, miR-221-3p, miR-486-5p, and miR-92a-3p are upregulated in both cells and EVs, promoting proliferation, migration, epithelial-to-mesenchymal transition (EMT), and immune evasion-all of which contribute to therapy resistance and an aggressive tumor phenotype. Conversely, tumor-suppressive miRNAs, such as miR-122-5p, miR-100, and miR-142-3p, are selectively exported from cancer cells via EVs, suggesting a protective mechanism by which cancer cells eliminate these tumor suppressors. This review focuses on the role of oncogenic and tumor-suppressive miRNAs within EVs and their implications for cervical cancer progression and treatment resistance. Additionally, it examines the dynamic interactions between the tumor microenvironment (TME) and EV cargo, as well as emerging therapeutic strategies that target EV-mediated miRNA transfer. These include the encapsulation of chemotherapeutic agents within EVs, the use of anti-miRs to silence oncogenic miRNAs, the delivery of tumor-suppressive miRNAs, the inhibition of EV release, and the targeting downstream miRNA-regulated proteins. While miRNA-based therapies remain in the early stages, they hold significant promise for overcoming treatment resistance and improving cervical cancer outcomes.
    Keywords:  Cervical cancer; Exosomes; Extracellular vesicles; Personalized medicine; Treatment resistance; miRNA
    DOI:  https://doi.org/10.1016/j.gene.2025.149467
  30. Microbiome Res Rep. 2025 ;4(1): 16
    The oncobiome; what, so what, now what?
    Munawar Abbas, Mark Tangney.
      Microbial communities inhabiting various body sites play critical roles in the initiation, progression, and treatment of cancer. The gut microbiota, a highly diverse microbial ecosystem, interacts with immune cells to modulate inflammation and immune surveillance, influencing cancer risk and therapeutic outcomes. Local tissue microbiota may impact the transition from premalignant states to malignancy. Characterization of the intratumoral microbiota increasingly reveals distinct microbiomes that may influence tumor growth, immune responses, and treatment efficacy. Various bacteria species have been reported to modulate cancer therapies through mechanisms such as altering drug metabolism and shaping the tumor microenvironment (TME). For instance, gut or intratumoral bacterial enzymatic activity can convert prodrugs into active forms, enhancing therapeutic effects or, conversely, inactivating small-molecule chemotherapeutics. Specific bacterial species have also been linked to improved responses to immunotherapy, underscoring the microbiome's role in treatment outcomes. Furthermore, unique microbial signatures in cancer patients, compared with healthy individuals, demonstrate the diagnostic potential of microbiota. Beyond the gut, tumor-associated and local microbiomes also affect therapy by influencing inflammation, tumor progression, and drug resistance. This review explores the multifaceted relationships between microbiomes and cancer, focusing on their roles in modulating the TME, immune activation, and treatment efficacy. The diagnostic and therapeutic potential of bacterial members of microbiota represents a promising avenue for advancing precision oncology and improving patient outcomes. By leveraging microbial biomarkers and interventions, new strategies can be developed to optimize cancer diagnosis and treatment.
    Keywords:  DNA; Microbiome; cancer; cancer therapy; tumor microenvironment
    DOI:  https://doi.org/10.20517/mrr.2024.89
  31. Front Immunol. 2025 ;16 1522417
    Pipelines for lymphocyte homeostasis maintenance during cancer immunotherapy.
    Bensu Du, Jin Geng, Bin Wu, Houru Wang, Ru Luo, Hanmeng Liu, Rui Zhang, Fengping Shan, Lei Liu, Shuling Zhang.
      In general, increasing lymphocyte entry into tumor microenvironment (TME) and limiting their efflux will have a positive effect on the efficacy of immunotherapy. Current studies suggest maintenance lymphocyte homeostasis during cancer immunotherapy through the two pipelines tumor-associated high endothelial venules and lymphatic vessels. Tumor-associated high endothelial venules (TA-HEVs) play a key role in cancer immunotherapy through facilitating lymphocyte trafficking to the tumor. While tumor-associated lymphatic vessels, in contrast, may promote the egress of lymphocytes and restrict their function. Therefore, the two traffic control points might be potential to maintain lymphocyte homeostasis in cancer during immunotherapy. Herein, we highlight the unexpected roles of lymphocyte circulation regulated by the two gateways for through reviewing the biological characters and functions of TA-HEVs and tumor-associated lymphatic vessels in the entry, positioning and exit of lymphocyte cells in TME during anti-tumor immunity.
    Keywords:  CD8 + T cells; immunotherapy; lymphocytes; tumor-associated high endothelial venules; tumor-associated lymphatic vessels
    DOI:  https://doi.org/10.3389/fimmu.2025.1522417
  32. J Immunother Cancer. 2025 Apr 09. pii: e010352. [Epub ahead of print]13(4):
    Neural crest-associated gene FOXD1 induces an immunosuppressive microenvironment by regulating myeloid-derived suppressor cells in melanoma.
    Qian Sun, Nina Wang, Juliane Poelchen, Mareike Peter, Daniel Novak, Feyza Gül Özbay Kurt, Rebekka Bitsch, Huizi Wu, Yiman Wang, Sandra Pardo, Rui Han, Shibo Liu, Lidong Gong, Yuxin Zhang, Kilian Wistuba-Hamprecht, Viktor Umansky, Jochen Sven Utikal.
       BACKGROUND: Neural crest-associated genes play pivotal roles in tumor initiation, progression, and the intricate dynamics of the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSC) within the TME are important in dampening T cell activity and contributing to resistance against immunotherapeutic interventions. The neural crest-associated gene Forkhead Box D1 (FOXD1) has been identified as an oncogenic factor that induces melanoma dedifferentiation and progression. However, the underlying mechanisms and the impact of FOXD1 on the antitumor immune response remain unclear.
    METHODS: To investigate the impacts of FOXD1 on the melanoma microenvironment, we analyzed publicly available datasets from multiple platforms, including TNMplot, TIMER2.0, etc. In addition, FOXD1 was overexpressed (OE) or knocked down in melanoma cells to identify its biological functions in vitro and in vivo. Flow cytometry and arginase activity assay were used to analyze the phenotype and function of MDSC. Western blot, reverse transcription-PCR, or ELISA assays were employed to analyze the expression of FOXD1 and its downstream effectors. In vivo experiments were conducted to investigate the role of FOXD1 in melanoma progression and the influence on MDSC accumulation within the TME.
    RESULTS: We demonstrate that increased FOXD1 levels inversely correlated with melanoma responsiveness to immunotherapy. Ex-vivo analyses unveiled that monocytes, exposed to conditioned medium from FOXD1-OE melanoma cells, effectively suppressed T cell proliferation and upregulated the expression of programmed death-ligand 1 (PD-L1) and other immunosuppressive factors. FOXD1 was identified as a direct regulator of interleukin 6 (IL6) expression, which is pivotal for MDSC induction. Blocking IL6 reversed MDSC-associated immunosuppression. Additionally, miR-581, a potential negative regulator of FOXD1, attenuated the impact of FOXD1 on IL6 expression and MDSC differentiation. In vivo experiments demonstrated that tumors derived from FOXD1 OE melanoma cells contained a significantly higher frequency of PD-L1+ MDSC compared with controls, while FOXD1 knockdown resulted in reduced tumor growth and diminished MDSC accumulation.
    CONCLUSION: Our study elucidated a novel function of FOXD1 in melanoma pathogenesis, highlighting its role in orchestrating the immunosuppressive TME by promoting the generation of MDSC via IL6 upregulation.
    Keywords:  Immunosuppression; Myeloid-derived suppressor cell - MDSC; Skin Cancer; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2024-010352
  33. Nanoscale Adv. 2025 Mar 28.
    Designer DNA nanocages modulate anti-oxidative and anti-inflammatory responses in tumor associated macrophages.
    Payal Vaswani, Dhiraj Bhatia.
      Cancer is a complex disease, with multiple treatment modalities, but no definitive cure. The tumor microenvironment contributes to the complexity of the disease by forming a niche of multiple cell types supporting each other to carry out various cellular functions. Tumor associated macrophages are one such kind of cells which support the tumor microenvironment via immunosuppression. DNA tetrahedron (TD), a widely explored DNA nanocage, has shown a lot of potential in therapeutics. However, the role of TD still remains quite unexplored in immunology. Here, we first establish the anti-oxidative and anti-inflammatory role of TD. We then proceed with using TD as a therapeutic agent in tumor associated macrophages by modulating the response of PD-L1. The findings of this work create a base for TD in biological applications such as cancer immunotherapy.
    DOI:  https://doi.org/10.1039/d4na01025f
  34. Cell Commun Signal. 2025 Apr 07. 23(1): 171
    Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies.
    Siwei Wang, Lu Qin, Furong Liu, Zhanguo Zhang.
      The cGAS-STING signaling pathway serves as a critical link between DNA sensing and innate immunity, and has tremendous potential to improve anti-tumor immunity by generating type I interferons. However, STING agonists have shown decreasing biotherapeutic efficacy in clinical trials. Tumor metabolism, characterized by aberrant nutrient utilization and energy production, is a fundamental hallmark of tumorigenesis. And modulating metabolic pathways in tumor cells has been discovered as a therapeutic strategy for tumors. As research concerning STING progressed, emerging evidence highlights its role in metabolic reprogramming, independent its immune function, indicating metabolic targets as a strategy for STING activation in cancers. In this review, we delve into the interplay between STING and multiple metabolic pathways. We also synthesize current knowledge on the antitumor functions of STING, and the metabolic targets within the tumor microenvironment (TME) that could be exploited for STING activation. This review highlights the necessity for future research to dissect the complex metabolic interactions with STING in various cancer types, emphasizing the potential for personalized therapeutic strategies based on metabolic profiling.
    DOI:  https://doi.org/10.1186/s12964-025-02169-0
  35. Cell Biol Toxicol. 2025 Apr 05. 41(1): 67
    Targeting B4GALT3 in BMSCs-EVs for Therapeutic Control of HCC via NF-κB pathway inhibition.
    Juncheng Guo, Kaiqiong Wang, Qigang Sun, Jun Liu, Jinfang Zheng.
      Examining the communications in the tumor microenvironment (TME) specific to hepatocellular carcinoma (HCC), this exploration looks into the role played by beta-1,4-Galactosyltransferase III (B4GALT3) in bone marrow mesenchymal stromal cell-derived extracellular vesicles (BMSCs-EVs) regarding the NF-κB pathway and the triggering of cancer-associated fibroblasts (CAF). Through a multidisciplinary approach combining transcriptome sequencing, bioinformatic analysis, and various experimental models, the involvement of B4GALT3 in regulating CAF activity by modulating NF-κB signaling was brought to light in our study. The outcomes suggest that targeting B4GALT3 could impede HCC cell migration and invasion, promote apoptosis, and dampen tumor progression and metastasis, offering novel insights into potential therapeutic strategies for combating HCC.
    Keywords:  Beta-1; Bone Marrow Mesenchymal Stromal Cells; Extracellular Vesicles; Hepatocellular Carcinoma; Tumor Microenvironment
    DOI:  https://doi.org/10.1007/s10565-025-10013-x
  36. JCI Insight. 2025 Apr 08. pii: e187531. [Epub ahead of print]
    Increased fatty acid delivery by tumor endothelium promotes metastatic outgrowth.
    Deanna N Edwards, Shan Wang, Kelby Kane, Wenqiang Song, Laura C Kim, Verra M Ngwa, Yoonha Hwang, Kevin C Ess, Mark R Boothby, Jin Chen.
      Metastatic outgrowth in distant microscopic niches requires sufficient nutrients, including fatty acids (FAs), to support tumor growth and to generate an immunosuppressive tumor microenvironment (TME). However, despite the important role of FAs in metastasis, the regulation of FA supply in metastatic niches has not been defined. In this report, we show that tumor endothelium actively promotes outgrowth and restricts anti-tumor cytolysis by transferring FA into developing metastatic tumors. We describe a process of transendothelial FA delivery via endosomes that requires mTORC1 activity. Thus, endothelial-specific targeted deletion of Raptor (RptorECKO), a unique component of the mTORC1 complex, significantly reduced metastatic tumor burden that was associated with improved markers of T cell cytotoxicity. Low dose everolimus that selectively inhibited endothelial mTORC1 improves immune checkpoint responses in metastatic disease models. This work reveals the importance of transendothelial nutrient delivery to the TME, highlighting a future target for therapeutic development.
    Keywords:  Cancer immunotherapy; Endothelial cells; Immunology; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.187531
  37. Commun Biol. 2025 Apr 04. 8(1): 562
    Targeting SCD triggers lipotoxicity of cancer cells and enhances anti-tumor immunity in breast cancer brain metastasis mouse models.
    Alessandro Sammarco, Giorgia Guerra, Katharina M Eyme, Kelly Kennewick, Yu Qiao, Joelle El Hokayem, Kevin J Williams, Baolong Su, Cagri Cakici, Hayk Mnatsakanyan, Valentina Zappulli, Steven J Bensinger, Christian E Badr.
      Breast cancer brain metastases (BCBM) are incurable, and new therapies are urgently needed. BCBM upregulates stearoyl-CoA desaturase (SCD), an enzyme that catalyzes the synthesis of monounsaturated fatty acids, suggesting a potential metabolic vulnerability. Here, we test the effect of a brain-penetrant, clinical-stage SCD inhibitor (SCDi) on breast cancer cells and mouse models of BCBM. We show that SCDi markedly reshapes the lipidome of breast cancer cells, resulting in endoplasmic reticulum stress, DNA damage, impaired DNA damage repair, and cytotoxicity. Importantly, SCDi alone or combined with a PARP inhibitor prolongs the survival of BCBM-bearing mice. Furthermore, pharmacological inhibition of SCD enhances antigen presentation by dendritic cells, increases interferon signaling, promotes the infiltration of cytotoxic T cells, and decreases the proportion of exhausted T cells and regulatory T cells (Tregs) in the tumor microenvironment (TME) in a syngeneic mouse model of BCBM. Additionally, SCDi reduces the engagement of immunosuppressive pathways, including the PD-1:PD-L1/PD-L2 and PVR/TIGIT axes in the TME. These findings suggest that SCD inhibition could be an effective strategy to both intrinsically reduce tumor growth and reprogram anti-tumor immunity in the brain microenvironment to treat BCBM.
    DOI:  https://doi.org/10.1038/s42003-025-07977-1
  38. Sci Transl Med. 2025 Apr 09. 17(793): eadr4458
    Succinate-loaded tumor cell-derived microparticles reprogram tumor-associated macrophage metabolism.
    Shuya Lu, Jiexiao Li, Yonggang Li, Shichuan Liu, Yutong Liu, Yue Liang, Xifen Zheng, Yiyang Chen, Jinghui Deng, Huafeng Zhang, Jingwei Ma, Jiadi Lv, Yugang Wang, Bo Huang, Ke Tang.
      The tumor microenvironment predominantly polarizes tumor-associated macrophages (TAMs) toward an M2-like phenotype, thereby inhibiting antitumor immune responses. This process is substantially affected by metabolic reprogramming; however, reeducating TAMs to enhance their antitumor capabilities through metabolic remodeling remains a challenge. Here, we show that tumor-derived microparticles loaded with succinate (SMPs) can remodel the metabolic state of TAMs. SMPs promote classical M1-like polarization of macrophages by enhancing glycolysis and attenuating the tricarboxylic acid (TCA) cycle in a protein succinylation-dependent manner. Mechanistically, succinate is delivered into the mitochondria and nucleus by SMPs, leading to succinylation of isocitrate dehydrogenase 2 (IDH2) and histone H3K122 within the lactate dehydrogenase A (Ldha) promoter region. Our findings provide a distinct approach for TAM polarization using cell membrane-derived microparticles loaded with endogenous metabolites, a platform that may be used more broadly for posttranslational modification-based tumor immunotherapy.
    DOI:  https://doi.org/10.1126/scitranslmed.adr4458
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