Aug 2026· Frontiers in Molecular Biosciences· Vol 13· 0 citations· 59 references
Medicine
TL;DR
Targeting the mechanisms regulating Treg recruitment, stability, or suppressive function may represent a promising strategy to enhance the efficacy of immunotherapies including Bacillus Calmette–Guérin therapy.
Abstract
Bladder cancer is characterized by a highly dynamic tumor microenvironment (TME) that critically influences tumor progression, immune evasion, and therapeutic responsiveness. Among the immune populations in the TME, regulatory T cells (Tregs) play a central role in maintaining immune tolerance but also suppress effective antitumor immunity. Increasing evidence suggests that Tregs accumulate in bladder tumors and are associated with disease progression and reduced response to immunotherapies. The bladder cancer TME provides multiple signals that promote Treg recruitment, expansion, and functional stabilization, including chemokine-mediated trafficking, metabolic adaptation, and cytokine-driven differentiation. Interactions between Tregs and other microenvironmental components, such as cancer-associated fibroblasts, tumor-associated macrophages, endothelial cells, and extracellular matrix elements, further reinforce the immunosuppressive niche that facilitates tumor survival and therapy resistance. Recent advances in single-cell transcriptomics, spatial profiling, and multiomics analyses have revealed substantial heterogeneity among tumor-infiltrating Tregs, suggesting the existence of specialized subsets with distinct functional and metabolic properties in the bladder TME. These emerging insights highlight the importance of understanding Treg–TME crosstalk in shaping the immune landscape of bladder cancer. Targeting the mechanisms regulating Treg recruitment, stability, or suppressive function may represent a promising strategy to enhance the efficacy of immunotherapies including Bacillus Calmette–Guérin therapy. This review summarizes recent advances in Treg biology in bladder cancer and highlights potential therapeutic strategies to modulate Treg-mediated immunosuppression in the TME.
Together, current evidence indicates that MDSCs represent context-dependent therapeutic nodes, while functional reprogramming, spatially resolved profiling, and patient stratification may improve immunotherapy outcomes.
Lisichen Zhu, Hui Liu, Sihan Zhang et al.· Cancer Letters· 0 citations
Despite the remarkable progress in cancer treatment, drug resistance and immune escape still severely limit clinical efficacy, largely due to tumor-induced immunosuppression. The main driver of this suppressive environment is myeloid-derived suppressor cells (MDSCs). Tumor-derived cytokines and chemokines can induce the expansion, activation, and recruitment of MDSCs, enabling them to effectively protect tumor cells from being recognized and cleared by immune cells by establishing an immunosuppressive barrier in peripheral lymphoid organs and the tumor microenvironment (TME). Upon arrival in the TME, MDSCs may alter their gene expression patterns through metabolic reprogramming, undergo skewed differentiation toward tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs), and initiate immunosuppression to promote tumor growth. Furthermore, they can shape an environment conducive to tumor development and metastasis through various nonimmune mechanisms. Currently, the overall understanding of the systematic integration of MDSC biological properties into therapeutic strategies remains underdeveloped. Therefore, in this review, we systematically summarize: (i) the classification and identification of MDSCs; (ii) their biological properties in the context of tumors and autoimmune diseases; (iii) tumor-promoting effects; (iv) genetic and signaling pathway regulatory mechanisms; (v) differentiation skewing in the TME; and (vi) cellular interactions with the TME. We also propose the clinical potential of MDSC-based predictive and prognostic biomarkers and outline strategies for targeting MDSCs for oncotherapy.
Rong-Jun Deng, Xiu-Yun Bai, Jue Yang et al.· Signal Transduction and Targ...· 0 citations
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable clinical success in hematological malignancies. However, its efficacy in solid tumors such as lung cancer remains constrained by the immunosuppressive tumor microenvironment (TME). Aberrant vascular architecture and dense stroma constitute major physical barriers that hinder CAR T cell infiltration. Additionally, an immunosuppressive cellular network, dominated by myeloid-derived suppressor cells and tumor-associated macrophages, further restricts CAR T cell expansion and function. Moreover, immune checkpoint signaling, inhibitory cytokines, dysregulated chemokine gradients, and metabolic reprogramming under hypoxia collectively create a hostile biochemical and metabolic milieu that drives CAR T cell dysfunction and exhaustion. This review systematically outlines these multifactorial barriers within the lung cancer TME and discusses emerging strategies, including combinatorial approaches, engineered CAR T designs, and microenvironment-modulating platforms, that aim to improve the therapeutic efficacy of CAR T cell therapy in lung cancer.
Lu Liu, Dan-Dan Liang, Cui Wang et al.· International Journal on Bio...· 0 citations
Mast cells (MCs) are tissue-resident immune cells that accumulate in the tumor microenvironment (TME) and display marked functional plasticity. Rather than acting through fixed pro-tumor or anti-tumor phenotypes, tumor-associated MCs acquire functional programs shaped by tumor type, spatial localization, disease stage, and local microenvironmental cues. In this review, we organize these dual roles around cellular crosstalk, mediator release, angiogenic and lymphangiogenic regulation, and extracellular matrix remodeling. Through these interconnected mechanisms, MCs may either promote tumor progression by reinforcing immunosuppression, limiting effector T cell activity, and supporting vascular, lymphatic, and stromal remodeling, or contribute to tumor suppression by promoting tumor cell apoptosis, antigen presentation, cytotoxic immune-cell recruitment, and anti-tumor mediator release. We also examine MC responses to various cancer treatments, including physical treatment modalities, chemotherapy, immunotherapy, targeted therapy, and CAR-based cell therapies, and discuss how these responses may influence therapeutic efficacy and treatment-related toxicity. Furthermore, we highlight emerging MC-targeted strategies that either suppress their chronic pro-tumor secretion or intentionally induce acute anti-tumor degranulation. By deciphering the dual nature of MCs in cancer, this review underscores the potential for reprogramming MCs to improve tumor treatment outcomes.
Dekun Song, G. Yan, Guolong Zhang· Cancer Immunology and Immuno...· 0 citations
Gastric cancer remains a highly lethal malignancy characterized by late diagnosis, limited therapeutic responsiveness, and a profoundly immunosuppressive tumor microenvironment. Among the diverse cellular components shaping this ecosystem, tumor-associated macrophages (TAMs) have emerged as central orchestrators of gastric carcinogenesis, metastatic dissemination, and therapeutic resistance. TAMs promote tumor initiation through inflammatory recruitment and polarization, facilitate invasion and angiogenesis via cytokines, matrix-remodeling enzymes, and exosomal cargo, and impair antitumor immunity by suppressing T-cell and natural killer cell function. In addition, TAMs contribute to resistance to immune checkpoint blockade by sustaining an immunosuppressive tumor immune microenvironment enriched in Tregs, myeloid-derived suppressor cells, and inhibitory mediators such as TGF-β, IL-10, and PD-L1. Recent advances further highlight the translational promise of macrophage-targeted strategies, including polarization reprogramming, recruitment blockade, and chimeric antigen receptor macrophage therapy. Previous reviews primarily focus on the general biological roles of TAMs, this review synthesizes newly emerging mechanisms of TAM-mediated immunotherapy resistance, including spatial heterogeneity, stromal-vascular remodeling, and exosomal crosstalk, with the latest clinical advances in macrophage-directed immunotherapies. We specifically highlight the translational potential and current clinical trial landscape of chimeric antigen receptor macrophage (CAR-M) therapy and targeted reprogramming strategies, providing a forward-looking perspective on overcoming immune checkpoint blockade resistance in gastric cancer.
Xiaofeng Cui, Xuerui Wang, Nan Jiang et al.· Frontiers in Immunology· 0 citations
Myeloid-derived suppressor cells (MDSCs) play an important role in colorectal cancer progression by contributing to the evasion of the antitumor immune response, treatment resistance, and metastasis formation. This integrative review aimed to analyze the mechanisms by which MDSCs promote the suppression of the antitumor immune response in colorectal cancer, as well as their contribution to disease progression. Studies published between 2020 and 2025 were analyzed using the PubMed and LILACS databases. The selected studies demonstrated that MDSCs employ different mechanisms to promote immunosuppression, including metabolic alterations that limit nutrient availability for immune cells, the production of cytotoxic molecules capable of impairing lymphocyte function, and the secretion of anti-inflammatory mediators that reduce immune system activity. Particularly, the gut microbiota and the presence of Fusobacterium nucleatum stimulate MDSC expansion and activity, contributing to the maintenance of chronic inflammation associated with colorectal cancer. Interactions between these cells and T lymphocytes, invariant natural killer cells, and neutrophils further intensify the immunosuppressive environment, while extracellular vesicles released by tumor and myeloid cells participate in feedback mechanisms that exacerbate immune dysfunction. These findings reinforce the central role of MDSCs in colorectal cancer progression and highlight their potential as therapeutic targets. However, the high heterogeneity of these cells and the lack of standardized methods for their identification remain challenges for their clinical application. Future studies integrating multiparametric flow cytometry, single-cell RNA sequencing, spatial analyses, and metabolomic approaches may provide a broader understanding of MDSC biology and contribute to the development of more specific and effective therapeutic strategies.
Maria Fernanda Imperio Pereira, Emilly Paschoal de Oliveira, Valéria de Lima Kaminski· Research, Society and Develo...· 0 citations
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