bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–08–31
28 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. The Multifaceted Role of Osteopontin in Modulating the Tumor Microenvironment.
  2. Lipid Metabolism Reprogramming in Cancer: Insights into Tumor Cells and Immune Cells Within the Tumor Microenvironment.
  3. Immunological Landscape and Molecular Therapeutic Targets of the Tumor Microenvironment in Hepatocellular Carcinoma.
  4. The significance of tumor microenvironment for immunotherapy in melanoma and non-melanoma skin cancer.
  5. Tumor Microenvironmental Dynamics in Shaping Resistance to Therapeutic Interventions in Melanoma: A Narrative Review.
  6. Targeting lactate metabolism in the tumor microenvironment: Immunomodulation and prospects for antitumor therapy.
  7. Domestication and feedback: bidirectional hijacking in pancreatic ductal adenocarcinoma microenvironment.
  8. Interactions between tumor microenvironment and resistance to transarterial and systemic treatments for HCC.
  9. Therapeutic Strategies Targeting Aerobic Glycolysis in Cancer and Dynamic Monitoring of Associated Metabolites.
  10. TSG6 promotes epithelial-mesenchymal transition and tumor-associated macrophage polarization through Smad2/3 and MAPK signaling by facilitating TSG6-CD44-TGFβR1 or EGFR complex formation.
  11. Targeting GABA signaling in the tumor microenvironment: implications for immune cell regulation and immunotherapy resistance.
  12. Glabridin-Gold(I) Complex as a Novel Immunomodulatory Agent Targeting TrxR and MAPK Pathways for Synergistic Enhancement of Antitumor Immunity.
  13. Why has immune "checkpoint" therapy failed in most clinical trials?
  14. Ferroptosis and immunotherapy: Breaking barriers in cancer treatment resistance.
  15. Exploring the Complexity of Cutaneous Squamous CellCarcinoma Microenvironment: Focus on Immune Cell Roles by Novel 3D In Vitro Models.
  16. Ordinary differential equation model of cancer-associated fibroblast heterogeneity predicts treatment outcomes.
  17. Impact of sympathetic nervous system on immune evasion in high-grade serous ovarian cancer: a review.
  18. Targeting the CD47-SIRPalpha checkpoint in multiple myeloma.
  19. Macrophage TBK1 signaling drives the development and outgrowth of breast cancer brain metastasis.
  20. Dual roles and therapeutic targeting of tumor-associated macrophages in tumor microenvironments.
  21. The role of Siglec-15 in tumor immunity: mechanism and therapy.
  22. Blood transfusion mediated tumor microenvironment remodeling in breast cancer.
  23. Plasma exosomes from individuals with type 2 diabetes drive breast cancer aggression in patient-derived organoids.
  24. The Role of Obesity in the Regulation of Immunosuppressive Cell Infiltration and Immunosurveillance in Cancers.
  25. Extracellular Vesicles Derived from Breast Cancer Cells: Emerging Biomarkers of Tumor Progression and Metastasis.
  26. Regulatory T cells in cancer anti-PD-(L)1 therapy.
  27. Adipocyte-derived factors induce adherent to suspension transition in breast and pancreatic cancer cells through lipid metabolic alteration.
  28. Unmasking immune checkpoint resistance in esophageal squamous cell carcinoma: Insights into the tumor microenvironment and biomarker landscape.
  1. Cancer Res. 2025 Aug 27.
    The Multifaceted Role of Osteopontin in Modulating the Tumor Microenvironment.
    Yu Gu, William J Muller.
      Osteopontin, a key structural protein in the extracellular matrix, plays a pivotal role in regulating the local tumor microenvironment and systemic immunity during cancer progression. Recognizing that tumor cells do not exist in isolation but rather interact with a multitude of stromal components that significantly influence patient outcomes and therapy responses, this review focuses on the role of osteopontin in non-tumor cells in the context of solid cancers and the associated phenotypic and mechanistic insights. We explore how osteopontin influences the behavior of various innate and adaptive immune cells, including natural killer cells, neutrophils, macrophages, dendritic cells, myeloid-derived suppressor cells, B cells, T cells, as well as structural stromal cells such as fibroblasts, endothelial cells, and adipocytes. The review highlights the roles of osteopontin in modulating these stromal cells and their multiaxial influence on tumorigenesis and metastasis. These complex interplays offer insights into potential diagnostic and therapeutic strategies around osteopontin/stromal-mediated pathways in cancer progression and recurrence.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1486
  2. Biomedicines. 2025 Aug 04. pii: 1895. [Epub ahead of print]13(8):
    Lipid Metabolism Reprogramming in Cancer: Insights into Tumor Cells and Immune Cells Within the Tumor Microenvironment.
    Rundong Liu, Chendong Wang, Zhen Tao, Guangyuan Hu.
      This review delves into the characteristics of lipid metabolism reprogramming in cancer cells and immune cells within the tumor microenvironment (TME), discussing its role in tumorigenesis and development and analyzing the value of lipid metabolism-related molecules in tumor diagnosis and prognosis. Cancer cells support their rapid growth through aerobic glycolysis and lipid metabolism reprogramming. Lipid metabolism plays distinct roles in cancer and immune cells, including energy supply, cell proliferation, angiogenesis, immune suppression, and tumor metastasis. This review focused on shared lipid metabolic enzymes and transporters, lipid metabolism-related oncogenes and non-coding RNAs (ncRNAs) involved in cancer cells, and the influence of lipid metabolism on T cells, dendritic cells (DCs), B cells, tumor associated macrophages (TAMs), tumor associated neutrophils (TANs), and natural killer cells (NKs) within TME. Additionally, the role of lipid metabolism in tumor diagnosis and prognosis was explored, and lipid metabolism-based anti-tumor treatment strategies were summarized, aiming to provide new perspectives for achieving precision medicine.
    Keywords:  diagnosis and prognosis; immune cells within the tumor microenvironment; lipid metabolism reprogramming; therapeutic strategy; tumor cells
    DOI:  https://doi.org/10.3390/biomedicines13081895
  3. Int J Mol Sci. 2025 Aug 13. pii: 7836. [Epub ahead of print]26(16):
    Immunological Landscape and Molecular Therapeutic Targets of the Tumor Microenvironment in Hepatocellular Carcinoma.
    Yusra Zarlashat, Abdul Ghaffar, Flora Guerra, Anna Picca.
      Hepatocellular carcinoma (HCC) is the most common liver cancer, with poor survival rates in advanced stages due to late diagnosis, tumor heterogeneity, and therapy resistance. The tumor microenvironment (TME) in HCC has a crucial role in tumor progression, characterized by a complex interaction of immune cells, stromal components, and immunosuppressive signaling pathways. Chronic inflammation driven by viral infections, metabolic dysfunction, and alcohol consumption triggers an immunosuppressive TME, promoting immune evasion and tumor growth. Immune cell populations, such as myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages, contribute to immunosuppression, while cytotoxic T lymphocytes and natural killer cells exert anti-tumor effects. Recent advances in immunotherapy, mainly immune checkpoint inhibitors (ICIs) targeting programmed death-ligand 1 and programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4, have revolutionized HCC treatment, though response rates remain limited. Combined therapies using tyrosine kinase inhibitors, anti-angiogenic agents, and ICIs improve patient outcomes. This review discusses the immunological mechanisms contributing to HCC progression, the role of immune cell subsets in tumor evasion, and therapeutic interventions, from conventional treatments to advanced immunotherapies. Ongoing clinical trials, barriers to effective treatment, and future directions to enhance HCC management and patient survival will also be overviewed.
    Keywords:  immune cells; immune checkpoint inhibitors; immune evasion; immunosuppression; immunotherapy; liver cancer
    DOI:  https://doi.org/10.3390/ijms26167836
  4. Immunol Med. 2025 Aug 25. 1-11
    The significance of tumor microenvironment for immunotherapy in melanoma and non-melanoma skin cancer.
    Taku Fujimura.
      Immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibody, have significantly changed the treatment landscape not only for unresectable melanoma but also for non-melanoma skin cancers. In addition, anti-PD-1 antibody administration methods have evolved and are now used in both the neoadjuvant and adjuvant settings. As these treatment strategies have been evaluated, it has become clear that understanding the role of the tumor microenvironment (TME) is critical to the success of anti-PD-1 antibody-based immunotherapy. For example, racial differences in the efficacy of immunotherapy in melanoma are influenced not only by tumor-related factors such as tumor mutational burden and microsatellite instability, but also by components of the TME, including tumor-associated macrophages, cancer-associated fibroblasts, and tumor-infiltrating lymphocytes (TILs), all of which can affect the therapeutic outcome of ICIs. Furthermore, studies conducted during the development of neoadjuvant therapies have shown that tumor-reactive TILs are densely localized within primary tumors and are closely associated with both treatment efficacy and the occurrence of immune-related adverse events. In this review, we discuss the therapeutic efficacy of currently available anti-PD-1 antibody-based immunotherapies for skin cancer and examine the role of the TME in influencing these therapeutic outcomes.
    Keywords:  Immune checkpoint inhibitors; anti-PD-1 antibody; combination therapy; tolerance; tumor microenvironment
    DOI:  https://doi.org/10.1080/25785826.2025.2550795
  5. Pharmaceuticals (Basel). 2025 Jul 22. pii: 1082. [Epub ahead of print]18(8):
    Tumor Microenvironmental Dynamics in Shaping Resistance to Therapeutic Interventions in Melanoma: A Narrative Review.
    Laci M Turner, Hanna Terhaar, Victoria Jiminez, Bailey J Anderson, Emily Grant, Nabiha Yusuf.
      Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed.
    Keywords:  CTLA-4; PD-L1; immune checkpoint inhibitors; melanoma; resistance; tumor microenvironments
    DOI:  https://doi.org/10.3390/ph18081082
  6. Int Immunopharmacol. 2025 Aug 23. pii: S1567-5769(25)01381-5. [Epub ahead of print]164 115390
    Targeting lactate metabolism in the tumor microenvironment: Immunomodulation and prospects for antitumor therapy.
    Jingnan Yan, Yafeng Qi, Yeyuan Liu, Xiaodan Jiang, Yangyang Li, Zhongyang Song, Liying Zhang, Zhiming Zhang.
      Disturbed lactate metabolism in the tumor microenvironment (TME) is a key factor driving malignant tumor progression. Recent studies have revealed that lactate is not only a metabolic by-product of glycolysis, but also an important signaling molecule that regulates tumor cell and immune cell functions. Lactate remodels TME through metabolic-signaling-immune interactions, inhibits the activity of effector immune cells, and promotes the expansion of immunosuppressive cells, thus weakening the anti-tumor immune response. This review systematically describes the regulatory network of lactate metabolism in the TME, focuses on analyzing the role of lactate on different immune cells, and explores innovative therapeutic strategies and clinical translational pathways that target lactate production/transport, neutralize the acidic environment, and multi-target remodeling of lactate homeostasis by traditional Chinese medicine (TCM), which will provide the basis for the formulation of precise antitumor treatment protocols based on metabolic remodeling and optimization of novel combinatorial therapies, and ultimately achieve an overall enhancement of the effectiveness of clinical cancer treatment.
    Keywords:  Immune cells; Lactate metabolism; Targeted therapy; Traditional Chinese medicine; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2025.115390
  7. Front Immunol. 2025 ;16 1585858
    Domestication and feedback: bidirectional hijacking in pancreatic ductal adenocarcinoma microenvironment.
    Yuxi Qiao, Haobo Yin, Yong Zhang, Jingdong Zhang, Qian Dong.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by a tumor microenvironment (TME) composed of a dense extracellular matrix, cancer-associated fibroblasts (CAFs), vasculature, neural elements, and immune cell populations. This complex network promotes tumor proliferation, invasion, metastasis, and resistance to immunotherapy and chemotherapy. The microenvironmental characteristics of the various PDAC subtypes are discussed in this review. And we examines the role of cancer cells in the TME, highlighting their ability to manipulate stromal components to serve as collaborators in tumor progression. Furthermore, we explored the formation mechanism of the immunosuppressive microenvironment in PDAC, paying attention on Inflammation and intrinsic genetic alterations, the regulatory effect of metabolic reprogramming, the contribution of CAFs and the role of immune cells in cancer cell metastasis. This review shows the role of soluble molecules and exosomes in facilitating PDAC progression and immune evasion within the microenvironment. In conclusion, we outline the novel therapeutic strategies that focus on the interaction between cancer cells and their microenvironment, with the objective of offering new insights for future precision medical interventions.
    Keywords:  cancer-associated fibroblasts; combination therapy; extracellular matrix; pancreatic ductal adenocarcinoma; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1585858
  8. Cancer Drug Resist. 2025 ;8 33
    Interactions between tumor microenvironment and resistance to transarterial and systemic treatments for HCC.
    Maria Stella Franzè, Francesca Saffioti, Vasileios K Mavroeidis.
      Hepatocellular carcinoma (HCC) is a malignant tumor originating from hepatocytes, often developing against a backdrop of chronic inflammation and liver fibrosis. The primary risk factor for HCC is cirrhosis, and early detection is crucial for improving outcomes. Despite advances in treatment, the prognosis remains poor, with a 5-year survival rate of approximately 15%-38%. Growing evidence highlights the critical role of the tumor microenvironment (TME) in modulating tumor initiation, growth, progression, and, in some cases, suppression. The TME is a complex ecosystem composed of immune cells, cancer-associated fibroblasts, extracellular matrix components, and other factors such as growth factors and cytokines. By shaping tumor cell behavior, the TME facilitates immune evasion and contributes to resistance to treatment. Tumor-associated immune cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, contribute to immune suppression and progression. On the other hand, immune activation via immune checkpoint inhibition has shown promise in improving outcomes, especially when combined with other treatments such as transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), and systemic therapies. Studies have demonstrated the potential of targeting the TME to enhance treatment efficacy, with immune modulation emerging as a key therapeutic strategy. This review explores the complex interactions within the TME in HCC, highlighting its role in therapy resistance and immune evasion. It also discusses current therapeutic approaches to target the TME to improve clinical outcomes in HCC patients.
    Keywords:  Hepatocellular carcinoma; drug resistance; extracellular matrix; immune checkpoint inhibitors; immune evasion; selective internal radiation therapy; systemic therapy; transarterial chemoembolization
    DOI:  https://doi.org/10.20517/cdr.2024.212
  9. Cells. 2025 Aug 19. pii: 1288. [Epub ahead of print]14(16):
    Therapeutic Strategies Targeting Aerobic Glycolysis in Cancer and Dynamic Monitoring of Associated Metabolites.
    Mengjie Hu, Kaijie Zheng, Lijiao Zhang, Yue Kan, Jiaqian Zhao, Dajing Chen.
      Cancer cells predominantly utilize aerobic glycolysis for energy production, preferentially converting glucose (Glu) to pyruvate (PA) and subsequently to lactate (LA). This metabolic reprogramming results in extracellular LA accumulation, acidifying the tumor microenvironment (TME) and facilitating tumor invasion and metastasis. The dynamics of Glu, PA, and LA are pivotal to tumor initiation and progression. This review comprehensively discussed therapeutic strategies targeting these key metabolites and systematically evaluates electrochemical and fluorescence-based techniques for their dynamic monitoring. We highlight the critical role of these monitoring approaches in advancing early cancer diagnosis, enabling personalized treatment, and accelerating anticancer drug development.
    Keywords:  aerobic glycolysis; electrochemical biosensor; fluorescent biosensor; metabolic biomarkers; metabolic reprogramming; targeted therapy
    DOI:  https://doi.org/10.3390/cells14161288
  10. Int J Biol Sci. 2025 ;21(11): 4701-4718
    TSG6 promotes epithelial-mesenchymal transition and tumor-associated macrophage polarization through Smad2/3 and MAPK signaling by facilitating TSG6-CD44-TGFβR1 or EGFR complex formation.
    Hyun-Ji Oh, Ga-Hong Min, Da-Eun Kim, Sol-Bi Shin, Hyungshin Yim.
      TSG6 is highly expressed during PLK1-induced epithelial-mesenchymal transition (EMT). However, the role of TSG6 in the tumor microenvironment (TME) remains poorly understood. We investigate the function and regulatory mechanisms of TSG6 in immune plasticity within the TME of lung adenocarcinoma (LUAD). The simultaneous high expression of TSG6 and PLK1 in LUAD patients was associated with lower survival rates. TSG6 and CD44 were markedly upregulated during EMT driven by TGF-b or active PLK1 in A549 and HCC827 cells. TSG6 treatment enhanced EMT by increasing N-cadherin and phosphorylated Smad2 levels. TSG6 depletion blocked the effects, which was restored upon TSG6 retreatment. Additionally, TSG6 treatment induced polarization of THP-1 monocytes into M2d tumor-associated macrophages (TAMs). In cocultures of THP-1 monocytes with A549 cells expressing TSG6, M2d-inducing factors in A549 cells and M2d markers in THP-1 cells were upregulated. Immunoprecipitation showed that TSG6 binds CD44, enhancing CD44's interaction with TGFbR or EGFR. In TSG6-treated LUAD cells, both total CD44 and its cleaved intracellular domain increased by activating TGFβR1-Smad2/3 and MAPK-ERK1/2-AP-1 pathways. Thus, TSG6 promotes EMT and M2d-TAMs polarization by activating TGFβR1/Smad and MAPK/ERK pathway through direct interaction between CD44 and TGFβR1 or EGFR.
    Keywords:  CD44; TSG6; invasiveness; tumor-associated macrophages
    DOI:  https://doi.org/10.7150/ijbs.115097
  11. Front Immunol. 2025 ;16 1645718
    Targeting GABA signaling in the tumor microenvironment: implications for immune cell regulation and immunotherapy resistance.
    Yuanqing Zhao, Jin Xu, Ke Yang, Li Bao.
      As an important inhibitory neurotransmitter, γ-aminobutyric acid (GABA) not only plays a key role in the central nervous system, but also has attracted wide attention in the tumor immune microenvironment in recent years. Studies have shown that tumor cells can synthesize GABA and use it to remodel the tumor microenvironment, thereby promoting the occurrence, development and metastasis of tumors. Although previous studies have revealed the important role of GABA in tumor immune escape, there are still many unknown areas of its mechanism, especially the heterogeneous manifestations in different tumor types and tissue environments. This review summarizes the immunomodulatory mechanisms of GABA in tumor-associated macrophages, CD8+ T cells and dendritic cells in the tumor immune microenvironment, and discusses its potential role in tumor immune escape and immunotherapy resistance, providing new ideas for the development of immunotherapeutic drugs targeting GABA receptors.
    Keywords:  GABA signaling; cancers; immune cell reg ulation; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1645718
  12. Adv Sci (Weinh). 2025 Aug 21. e04729
    Glabridin-Gold(I) Complex as a Novel Immunomodulatory Agent Targeting TrxR and MAPK Pathways for Synergistic Enhancement of Antitumor Immunity.
    Zhaoran Wang, Meiyu Wang, Qiong Chen, Mengshi Wang, Fuwei Li, Lin Lv, Zhenfan Wen, Zhongren Xu, Yixia Yang, Chunyang Bi, Wukun Liu.
      Metal-based drugs have been utilized as immunomodulatory agents in combination with cancer immunotherapies to induce tumor immunogenicity. However, the immunosuppressive tumor microenvironment significantly hinders the efficacy of these immunomodulatory agents from promoting antitumor immune responses. Herein, a novel metal-based immunomodulatory agent, 6d, is developed by integrating N-heterocyclic carbene gold(I) [NHC-Au(I)] with the natural product glabridin (GLA). Complex 6d aims to promote tumor immunogenicity while suppressing immunosuppression, by targeting thioredoxin reductase (TrxR) and the mitogen-activated protein kinase (MAPK) pathways. Notably, 6d enhances dendritic cell (DC) maturation while reducing myeloid-derived suppressor cells (MDSCs), M2-type macrophages, and regulatory T cells (Tregs) in liver cancer. Moreover, 6d exhibits a synergistic effect of gold center and GLA, suppressing programmed cell death 1 ligand 1 (PD-L1) expression in tumor cells while promoting granzyme B (GzmB) production in T cells. These findings suggest that dual inhibition of TrxR and MAPK may provide a synergistic strategy to stimulate antitumor immunity while mitigating the immunosuppressive tumor microenvironment. Overall, this study warrants further researches to determine therapeutic efficacy of 6d as an immunomodulatory agent in combination with cancer immunotherapies.
    Keywords:  Immunomodulatory agent; immunosuppressive microenvironment; metal complex; tumor immunotherapy
    DOI:  https://doi.org/10.1002/advs.202504729
  13. J Immunother Cancer. 2025 Aug 27. pii: e012457. [Epub ahead of print]13(8):
    Why has immune "checkpoint" therapy failed in most clinical trials?
    Xuan Yang, Lieping Chen.
      Cancer immunotherapy targeting the PD-1/PD-L1 pathway has demonstrated efficacy across a range of common solid tumors and some hematopoietic malignancies. Despite these groundbreaking successes, the clinical development of other 'checkpoint inhibitors' targeting molecules like TIM-3, TIGIT, ICOS and others, has largely fallen short, often showing minimal clinical benefit even in combination with anti-PD therapy. This article explores three key hypotheses that help explain the disparity in therapeutic success: (1) the absence of tumor- specific immunosuppressive logic in many checkpoint targets, (2) the dominance-but not redundancy-of immune evasion mechanisms within the tumor microenvironment (TME), and (3) the emergence of therapy-induced resistance. This is not intended as a comprehensive review of the literature. Instead, it highlights select evidence to explain past failures and to illuminate a more strategic, biologically informed path forward.
    Keywords:  Immune modulatory; Immunosuppression; Immunotherapy; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2025-012457
  14. Crit Rev Oncol Hematol. 2025 Aug 19. pii: S1040-8428(25)00295-1. [Epub ahead of print]214 104907
    Ferroptosis and immunotherapy: Breaking barriers in cancer treatment resistance.
    Mohammad Ebrahimnezhad, Amir Valizadeh, Bahman Yousefi.
      Cancer treatment has been revolutionized by immunotherapy; however, its efficacy is often hindered by intrinsic or acquired resistance mechanisms within the tumor microenvironment. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has recently emerged as a potent strategy to overcome these therapeutic barriers. This review explores the dynamic interplay between ferroptosis and immune responses, highlighting how ferroptosis modulates macrophage polarization, T cell activity, and cytokine signaling to reshape the immunosuppressive tumor milieu. The induction of ferroptosis enhances tumor immunogenicity, facilitates T cell infiltration, and sensitizes resistant cancer cells to immune checkpoint inhibitors, CAR T-cell therapy, and monoclonal antibodies. Additionally, targeting ferroptosis pathways disrupts immune escape mechanisms mediated by regulatory T cells and myeloid-derived suppressor cells, further augmenting immunotherapeutic outcomes. By dissecting the molecular and metabolic underpinnings of ferroptosis and its integration with immune strategies, this article underscores its potential to overcome cancer immunotherapy resistance and pave the way for innovative combinatorial treatments.
    Keywords:  Ferroptosis; Immune Checkpoint inhibitor; Immunotherapy; Lipid peroxidation; Tumor Microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104907
  15. Life (Basel). 2025 Jul 23. pii: 1170. [Epub ahead of print]15(8):
    Exploring the Complexity of Cutaneous Squamous CellCarcinoma Microenvironment: Focus on Immune Cell Roles by Novel 3D In Vitro Models.
    Marika Quadri, Marco Iuliano, Paolo Rosa, Giorgio Mangino, Elisabetta Palazzo.
      Non-melanoma skin cancer (NMSC), comprising basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), represents the most common type of cancer worldwide, particularly among Caucasians. While BCC is locally invasive with minimal metastatic potential, cSCC is a highly aggressive tumor with a significant potential for metastasis, particularly in elderly populations. Tumor development and progression and the metastasis of cSCC are influenced by a complex interplay between tumor cells and the tumor microenvironment. Recent research highlights the importance of various immune cell subsets, including T cells, tumor-associated macrophages (TAMs), and dendritic cells, in influencing tumor progression, immune evasion, and treatment resistance. This review outlines key regulatory mechanisms in the immune tumor microenvironment (TME) of cSCC and explores the role of cytokines, immune checkpoints, and stromal interactions. We further discuss the relevance of three-dimensional (3D) in vitro models such as spheroids, organoids, and tumor-on-chip systems as tools to mimic immune-tumor interactions with higher physiological relevance, such as macrophage activation and polarization against cSCC cells. Globally, 3D models offer new opportunities for immunotherapy screening and mechanistic studies. Understanding the immune landscape in cSCC through advanced modeling techniques holds strong clinical potential for improving diagnostic and therapeutic strategies.
    Keywords:  3D models; cutaneous squamous cell carcinoma; immune cells; immune evasion; immunotherapy; non-melanoma skin cancer; organoids; spheroids; tumor microenvironment; tumor-associated macrophages; tumor-on-chip
    DOI:  https://doi.org/10.3390/life15081170
  16. NPJ Syst Biol Appl. 2025 Aug 23. 11(1): 96
    Ordinary differential equation model of cancer-associated fibroblast heterogeneity predicts treatment outcomes.
    Junho Lee, Eunjung Kim.
      Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME). CAF phenotypes are highly heterogeneous and exert anti- and protumorigenic effects. We present a mathematical model that describes cancer-immune-CAF interactions and exploits the heterogeneity of CAF phenotypes to predict cancer progression and treatment response. By simulating multiple treatment options, including targeted monotherapies alone, two different immunotherapies, and a combination of therapies, we have found that CAF composition can impact treatment outcomes, potentially resulting in comparable effectiveness of single-drug treatments and combinatorial approaches or even the ineffectiveness of multicombination therapies. These findings suggest that CAF composition can be a promising indicator, in some cases guiding the choice towards less invasive therapies without compromising effectiveness. Our model indicates that accounting for CAF characteristics might facilitate the matching of targeted treatments, supporting clinical decision-making.
    DOI:  https://doi.org/10.1038/s41540-025-00578-y
  17. Front Oncol. 2025 ;15 1644895
    Impact of sympathetic nervous system on immune evasion in high-grade serous ovarian cancer: a review.
    Ruiyuan Yu, Yumeng Li, Runze Jiang, Chunxiao Dang, Fengting Zhai.
      As the most frequent and aggressive subtype of ovarian cancer, high-grade serous ovarian cancer (HGSOC) often advances unnoticed due to its subtle early symptoms, which in turn leads to a significantly low five-year survival rate. The process of immune evasion, often achieved by constructing an immunosuppressive microenvironment through various pathways, stands as a critical feature of tumor biology. At the same time, emerging studies reveal a strong association between the sympathetic nervous system (SNS) and immune regulation in the tumor microenvironment (TME). In HGSOC, SNS activation releases neurotransmitters like norepinephrine, which affect immune cells, suppress their functions, weaken anti-tumor responses, and promote the recruitment and activation of immunosuppressive cells. By recruiting immune-suppressive cells, altering the extracellular matrix to construct physical barriers, and increasing pro-angiogenic signals, the SNS reshapes the tumor microenvironment in a way that hampers immunotherapy. Clinically, higher levels of SNS activation are linked to worse outcomes and therapeutic resistance in HGSOC. Additionally, preclinical studies demonstrate that targeting the SNS using β-adrenergic receptor inhibitors can improve immune activation and enhance treatment responses. Moving forward, research needs to further examine SNS mechanisms to support the development of advanced therapeutic strategies.
    Keywords:  high-grade serous ovarian cancer; immune evasion; immunotherapy; sympathetic nervous system; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2025.1644895
  18. Discov Oncol. 2025 Aug 25. 16(1): 1616
    Targeting the CD47-SIRPalpha checkpoint in multiple myeloma.
    Tao Ming Sim, Wee Joo Chng, Haiyan Liu, Sanjay de Mel.
      Immune evasion is a hallmark of cancer and there is mounting evidence that the tumor microenvironment (TME) plays a role in the pathogenesis of haematologic malignancies as well as treatment resistance. Macrophages play a central role in anti-tumor immunity, and dysregulation of macrophage mediated phagocytosis has recently emerged as a key player in blood cancers. The integrin associated protein CD47 is expressed in a variety of cancers and interacts with its ligand, signal regulatory protein α (SIRPα) expressed on macrophages, resulting in down regulation of macrophage-mediated phagocytosis. CD47 is highly expressed in various cancers including multiple myeloma (MM). It is therefore postulated that blockade of the CD47-SIRPα immune checkpoint has the potential to 're-awaken' macrophage mediated phagocytosis of MM plasma cells. In this review, we provide our perspective on the key pre-clinical data supporting the CD47-SIRPα axis as a therapeutic target in MM. We subsequently discuss the ongoing clinical trials which may provide the basis for future clinical translation of these agents. We also highlight key gaps in our knowledge of macrophage biology in MM which need to be addressed by future research. Finally, we present potential future directions for translational research and personalized application of macrophage-based immunotherapy in MM.
    Keywords:  CD47; Checkpoint inhibition; Macrophage; Multiple myeloma; SIRPalpha
    DOI:  https://doi.org/10.1007/s12672-025-03312-6
  19. Proc Natl Acad Sci U S A. 2025 Aug 26. 122(34): e2420793122
    Macrophage TBK1 signaling drives the development and outgrowth of breast cancer brain metastasis.
    Fatima Khan, Yang Liu, Donovan Whitfield, Lizhi Pang, Heba Ali, Yuyun Huang, Fei Zhou, Robert S Hagan, Katie Frenis, R Grant Rowe, Peiwen Chen.
      Tumor-associated macrophages (TAMs) are the predominant immune cells in the tumor microenvironment that promote breast cancer brain metastasis (BCBM). Here, we identify TANK-binding kinase (TBK1) as a critical signaling molecule enriched and activated in TAMs of BCBM tumors, playing an indispensable role in BCBM development and metastatic outgrowth in the brain. Mechanistically, BCBM cell-secreted matrix metalloproteinase 1 binds to protease-activated receptor 1 and integrin αVβ5 on macrophages, leading to TBK1 activation mediated by the nuclear factor-kappa B pathway. Reciprocally, TBK1-regulated TAMs produce granulocyte-macrophage colony-stimulating factor (GM-CSF) to drive breast cancer cell epithelial-mesenchymal transition, migration, and invasion, ultimately contributing to BCBM development and brain metastatic outgrowth. Inhibition of TBK1 signaling in TAMs or GM-CSF receptor in cancer cells impedes BCBM development and brain metastatic outgrowth. Correspondingly, the TBK1-GM-CSF signaling axis correlates with lower overall survival in patients with BCBM. Thus, TBK1-mediated tumor-TAM symbiotic interaction provides a promising therapeutic target for patients with BCBM.
    Keywords:  GM-CSF; TBK1; brain metastasis; breast cancer; macrophages
    DOI:  https://doi.org/10.1073/pnas.2420793122
  20. Signal Transduct Target Ther. 2025 Aug 25. 10(1): 268
    Dual roles and therapeutic targeting of tumor-associated macrophages in tumor microenvironments.
    Jiasheng Xu, Lei Ding, Jianfeng Mei, Yeting Hu, Xiangxing Kong, Siqi Dai, Tongtong Bu, Qian Xiao, Kefeng Ding.
      Tumor-associated macrophages (TAMs), derived from circulating monocytes recruited to tumor sites via chemotactic signals such as C-C motif ligand 2 (CCL2) and colony-stimulating factor-1 (CSF-1), are pivotal components of the tumor microenvironment (TME). Functionally polarized into distinct subtypes, TAMs play dual roles: proinflammatory M1-type TAMs enhance antitumor immunity through the secretion of cytokines such as interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α) and direct tumor cell cytotoxicity, whereas M2-type TAMs promote tumor progression by facilitating angiogenesis, metastasis, and immunosuppression. This polarization is dynamically regulated by different cytokines, various signaling pathways, and metabolic cues within the TME. Spatial distribution analyses revealed that M2-like TAMs predominantly infiltrate hypoxic and stromal regions, where they secrete factors such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), and matrix metalloproteinases (MMPs) to remodel the extracellular matrix and suppress immune responses via programmed death-ligand 1 (PD-L1) and arginase-1 upregulation. Crucially, TAMs interact extensively with immune cells; M2-TAMs secrete interleukin-10 (IL-10) and TGF-β to inhibit cytotoxic T lymphocytes while expanding regulatory T (Treg) cells and impairing natural killer (NK) cell function via altered antigen presentation. Conversely, M1-TAMs synergize with dendritic cells to enhance T-cell priming. Therapeutically, targeting TAMs offers promising strategies, including colony-stimulating factor-1 receptor (CSF-1R) inhibitors, CCL2 antagonists, and nanoparticle-mediated repolarization of M2-TAMs toward the M1 phenotype. Emerging genetic approaches, such as clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9 (CRISPR-Cas9) editing, aim to disrupt protumorigenic pathways in TAMs. Additionally, TAM-related biomarkers (e.g., CD206 and CD163) are being evaluated for their prognostic and predictive utility in immunotherapies. Despite progress, challenges persist owing to TAM plasticity and TME heterogeneity across cancers. This review synthesizes TAM biology, immune crosstalk, and therapeutic advancements, providing a foundation for novel oncology strategies aimed at reprogramming TAMs to overcome treatment resistance and improve clinical outcomes.
    DOI:  https://doi.org/10.1038/s41392-025-02325-5
  21. Mol Cancer Ther. 2025 Aug 20.
    The role of Siglec-15 in tumor immunity: mechanism and therapy.
    Lin Li, Li Wang, Qin Liu, Yingchun Ye, Qian Lei, Chengwen Li, Xiyuan Guo, Siji Nian, Qing Yuan.
      Siglec-15, a member of the sialic acid-binding immunoglobulin-like lectins (Siglecs) family, has emerged as a pivotal immunosuppressive mediator and a promising therapeutic target in cancer immunotherapy. This transmembrane glycoprotein orchestrates multifaceted biological processes, such as osteoclastogenesis regulation, bone remodeling, and tumor-associated macrophage (TAM)-mediated T cell immunosuppression. Notably, Siglec-15 exhibits non-redundant expression with programmed death-ligand 1 (PD-L1), suggesting its compensatory role in immune evasion mechanisms within PD-L1-negative tumor microenvironment (TME). This review delineates the molecular architecture of Siglec-15 and elucidates its pleiotropic regulatory mechanisms. Particular emphasis is placed on deciphering its immunomodulatory functions within tumor ecosystems, while critically evaluating emerging therapeutic modalities targeting Siglec-15, spanning from preclinical validation to ongoing clinical trials.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0323
  22. Acta Histochem. 2025 Aug 22. pii: S0065-1281(25)00061-3. [Epub ahead of print]127(4): 152289
    Blood transfusion mediated tumor microenvironment remodeling in breast cancer.
    Qinan Yin, Shunshun Zhang, Mouna Ouchari, Pei Wang, Anshun Zhao, Li Zeng, Jingjing Wang, Kaiyuan Yao, Siya Tang, Haodi Ma, Anne-Catherine Girondin, Hecai Yang, Xuewei Zheng, Zhifeng Qu.
      Blood transfusions play a critical role in breast cancer management, particularly in addressing perioperative blood loss and chemotherapy-induced anemia. However, emerging evidence suggests that transfusions may adversely affect oncologic outcomes by inducing transfusion-related immunomodulation (TRIM) and altering the tumor microenvironment (TME). TRIM suppresses cytotoxic immune responses, potentially facilitating tumor progression-especially in aggressive subtypes such as triple-negative breast cancer (TNBC) and HER2-positive cancers. Additionally, transfusions can paradoxically exacerbate tumor hypoxia by increasing blood viscosity and impairing microvascular perfusion, thereby reducing the effectiveness of chemotherapy, radiotherapy, and immunotherapy. This review examines the dual role of blood transfusions in breast cancer, emphasizing both their clinical benefits and potential risks. We analyze their impact on treatment resistance and tumor progression and discuss strategies to mitigate associated risks, including leukoreduction, erythropoiesis-stimulating agents (ESAs), intravenous iron supplementation, and blood conservation techniques. Furthermore, we highlight the importance of personalized transfusion approaches guided by tumor subtype, immune status, and relevant biomarkers such as tumor-infiltrating lymphocytes (TILs), PD-L1 expression, and circulating tumor DNA (ctDNA). Future research should focus on optimizing transfusion timing, implementing biomarker-driven protocols, and developing immune-modulating interventions to counteract TRIM. A personalized, evidence-based transfusion strategy may ultimately enhance treatment efficacy and improve long-term outcomes in breast cancer care.
    Keywords:  Blood transfusion; Breast cancer; Personalized transfusion strategy; Transfusion-related immunomodulation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.acthis.2025.152289
  23. Commun Biol. 2025 Aug 26. 8(1): 1276
    Plasma exosomes from individuals with type 2 diabetes drive breast cancer aggression in patient-derived organoids.
    Christina S Ennis, Michael Seen, Andrew Chen, Heejoo Kang, Adrian Ilinski, Kiana Mahdaviani, Naomi Y Ko, Stefano Monti, Gerald V Denis.
      Women with obesity-driven type 2 diabetes (T2D) face worse breast cancer outcomes, yet metabolic status does not fully inform current standards of care. We previously identified plasma exosomes as key drivers of tumor progression; however, their effect on immune cells within the tumor microenvironment (TME) remains unclear. Using a novel patient-derived organoid (PDO) system that preserves native tumor-infiltrating lymphocytes (TILs), we show that T2D plasma exosomes induce a 13.6-fold expansion of immunosuppressive TILs relative to nondiabetic controls. This immune dysfunction may promote micrometastatic survival and resistance to checkpoint blockade, a known issue in T2D cancer patients. Tumor-intrinsic analysis revealed a 1.5-fold increase in intratumoral heterogeneity and 2.3-fold upregulation of aggressive signaling networks. These findings reveal how T2D-associated metabolic dysregulation alters tumor-immune crosstalk through previously underappreciated exosomal signaling, impairing antitumor immunity and accelerating progression. Understanding these dynamics could inform tailored therapies for this high-risk, underserved patient population.
    DOI:  https://doi.org/10.1038/s42003-025-08663-y
  24. Diseases. 2025 Aug 21. pii: 271. [Epub ahead of print]13(8):
    The Role of Obesity in the Regulation of Immunosuppressive Cell Infiltration and Immunosurveillance in Cancers.
    Chunye Zhang, Keyao Zhu, Jiazheng Liu, Ming Yang.
      Cancer is a leading cause of death worldwide, causing about 10 million deaths annually. Obesity contributes to cancer progression by inducing chronic inflammation, immunosuppressive microenvironment, metabolic dysfunction, and therapeutic resistance. Accumulating evidence shows that obesity can advance the infiltration of immunosuppressive cells and ameliorate the function and cytotoxicity of tumor-killing cells such as natural killer cells, natural killer T cells, macrophages, and CD8 T cells in cancer patients, resulting in cancer progression. Understanding the molecular signaling pathways involved in obesity-induced immunosuppression and cancer cell proliferation enables us to screen new biomarkers for cancer early diagnosis and improve anti-tumor therapeutic efficacy in obese patients with cancer. In this review, we first review the molecular mechanisms by which obesity induces the immunosuppressive landscape in the tumor microenvironment and some key obesity-associated factors causing immunotherapeutic suppression and metabolic dysfunction. Then, the application of natural products in the treatment of obesity and obesity-associated cancers is summarized. In addition, we discuss the contradictory functions of obesity in cancer risk and treatment outcome. The potent roles of precision medicine and artificial intelligence in the management of obesity-related cancers are highlighted.
    Keywords:  artificial intelligence; cancer; clinical trials; immune cell infiltration; immunosuppression; natural medicines; obesity
    DOI:  https://doi.org/10.3390/diseases13080271
  25. Biomolecules. 2025 Aug 19. pii: 1195. [Epub ahead of print]15(8):
    Extracellular Vesicles Derived from Breast Cancer Cells: Emerging Biomarkers of Tumor Progression and Metastasis.
    Sona Bernatova, Andreas Nicodemou, Michaela Cehakova, Lubos Danisovic, Martin Bohac.
      Breast cancer (BC) remains one of the most prevalent and life-threatening malignancies worldwide, marked by significant heterogeneity and complex mechanisms of progression. Despite major advances in understanding its molecular and cellular basis, the processes driving tumor progression and metastasis continue to challenge effective treatment. Among the emerging research areas, extracellular vesicles (EVs) have gained considerable attention for their key role in intercellular communication and their contribution to cancer biology. In BC, tumor cell-derived EVs are implicated in multiple processes that promote disease progression, including tumor growth, remodeling of the tumor microenvironment, and facilitation of metastasis. By transferring oncogenic signals to recipient cells, EVs critically shape the metastatic niche and support the spread of cancer cells to distant organs. Recent studies highlight the diverse functions of BC-derived EVs in modulating immune responses, inducing angiogenesis, and enhancing cancer cell invasiveness. This review explores the role of BC-derived EVs in tumor progression and metastasis. We discuss their molecular composition, mechanisms of action, and impact on the tumor microenvironment, aiming to provide insights into their role in BC pathophysiology and discuss potential clinical applications. A deeper understanding of the complex interplay between EVs and cancer progression may pave the way for innovative strategies to combat BC and improve patient outcomes.
    Keywords:  breast cancer; cancer biology; extracellular vesicles
    DOI:  https://doi.org/10.3390/biom15081195
  26. Hum Cell. 2025 Aug 25. 38(5): 150
    Regulatory T cells in cancer anti-PD-(L)1 therapy.
    Keywan Mortezaee.
      Regulatory T cell (Treg) immunome profile and targets in antiprogrammed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) is a subject of extensive research, but there are still complexities in the area due to the nature of tumor microenvironment (TME). TME of solid tumors contains factors exerting a range of effects on Tregs including development, recruitment, expansion, stability and their immunosuppressive activity. Anti-PD-1 secondarily causes replenishment of intratumoral Tregs, which further intensify tumor immunosuppression. Besides, Treg depletion may also compromise immune checkpoint inhibitor (ICI) efficacy in addition to its other adversarial effects. Thus, a desired ICI booster is to use agents preferentially acting on intratumoral Tregs. Modulation of hypoxia, and regulation of Treg-related cytokines, chemokines, receptors and chromatin modifying factors in tumor TME provide supplementary approaches to anti-PD-(L)1. Factors acting on Tregs have diverse or even dual functions in TME. Treg expansion inhibitory and immunosuppressive tumor-associated macrophage (TAM) recruitment stimulatory effects of stimulator of interferon genes (STING), effector suppressor Treg activating and tumor-specific CD8+ T cell stimulatory effects of interleukin type 2 receptor alpha (IL-2Rα, also called CD25), cell type-dependent dual activities of CXCR3 and inducible T cell costimulatory (ICOS), exposure time-dependent dual effects of glucocorticoid-induced TNFR-related protein (GITR) and CD70 on Tregs and T cells, and exposure level-dependent dual activities of IFN-γ on Tregs are examples require consideration in designing Treg-based strategies. The main direction of this review is to provide updated information about targeting modulators of intratumoral Tregs with agents/compounds aiming to expand anti-PD-(L)1 efficacy and durability in solid tumors.
    Keywords:  Immune checkpoint inhibitor (ICI); Programmed cell death-1 (PD-1); Programmed cell death-ligand 1 (PD-L1); Regulatory T cell (Treg)
    DOI:  https://doi.org/10.1007/s13577-025-01280-1
  27. Sci Rep. 2025 Aug 20. 15(1): 30552
    Adipocyte-derived factors induce adherent to suspension transition in breast and pancreatic cancer cells through lipid metabolic alteration.
    Doru Kwon, Hyun Woo Park, Byung Soh Min, Junjeong Choi.
      Adipocytes play a dynamic role in the tumor microenvironment (TME) by acting as facilitators, providing cytokines and metabolites that regulate cancer progression and metastasis. Despite metastasis being a major contributor to cancer-associated mortality, our understanding of how adipocytes influence this process remains limited. This study aims to elucidate the regulatory mechanism of Adherent to Suspension Transition (AST) reprogramming within the adipocyte, driven by anchorage dependency. AST facilitates the conversion of adherent tumor cells into suspension cells, thereby contributing to the generation of circulating tumor cells (CTCs). We have evaluated generating AST cells from primary tumors using a dissemination assay that mimics CTCs in vitro. Additionally, we examined AST cell formation when incubated with human adipocyte-conditioned media (ADCM) using the InCucyte live-cell imaging system. Through this approach, we effectively assessed the impact of the tumor-adipocyte interactions on CTC formation from the perspective of AST. As a metastasis-initiating marker, CD36 is pivotal in fatty acid (FA) acquisition and regulates lipid metabolic remodeling during the AST. The generation of AST cells through AST reprogramming is controlled by fatty acid oxidation (FAO), and pharmacological blockade of CD36 and FAO significantly reduced AST cell generation. This demonstrates that CD36 plays a key role in the early stages of AST-induced dissemination. Additionally, promoting cancer cell aggressiveness through ADCM enhances metastatic potency and upregulates the expression of AST reprogramming factors. Inhibition of lipid metabolism not only suppresses AST cell formation but also decreases survival in suspension. This indicates that exogenous lipid uptake and FAO via CD36 play crucial roles in the metastasis process, facilitating the dissemination of primary tumors into the bloodstream. Adipocytes contribute to cancer progression by supplying various metabolites to cancer cells. While primary tumors predominantly rely on glucose as a major energy source, cellular remodeling during dissemination shifts metabolic dependency toward lipids. In the TME, where adipocytes are abundant, tumor cells acquire FA through CD36-mediated uptake for metabolic adaptation. This shift to lipid metabolism is essential for AST, and thus, targeting lipid metabolism via inhibition of CD36 and FAO could serve as a potential therapeutic strategy for AST.
    Keywords:  AST; Adipocytes; CD36; Circulating tumor cell; Lipid metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1038/s41598-025-13309-4
  28. World J Gastrointest Oncol. 2025 Aug 15. 17(8): 109489
    Unmasking immune checkpoint resistance in esophageal squamous cell carcinoma: Insights into the tumor microenvironment and biomarker landscape.
    Zhe Wang, Rui-Ying Zhang, Yi-Fan Xu, Bing-Tong Yue, Jia-Yi Zhang, Feng Wang.
      Esophageal squamous cell carcinoma (ESCC) remains a daunting global health concern. It is marked by aggressive progression and poor survival. While immunotherapy has emerged as a promising treatment modality, both primary and acquired resistance continue to limit its clinical impact, leaving many patients without durable benefits (e.g., CheckMate-648, ESCORT-1st). This review explains resistance mechanisms and suggests new strategies to improve outcomes. These mechanisms include immunosuppressive cells (Treg cells, myeloid-derived suppressor cells), inhibitory cytokines, molecular alterations involving programmed death 1/programmed death-ligand 1 signaling, and impaired antigen presentation. We also highlight key clinical trials-for example, CheckMate-648 and ESCORT-1st-that reveal both the potential and pitfalls of current immune checkpoint blockade strategies, underscoring the need for robust predictive biomarkers. Moreover, we examine cutting-edge tactics to overcome resistance, including combination regimens, tumor microenvironment remodeling, and tailored treatment approaches rooted in the patient's unique genomic and immunologic landscape.
    Keywords:  Biomarkers; Esophageal squamous cell carcinoma; Immune checkpoint blockade; Immunotherapy resistance; Tumor microenvironment
    DOI:  https://doi.org/10.4251/wjgo.v17.i8.109489
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