Jul 2026· International Reviews of Immunology· pp.
1-25
· 1 citation· 139 references
Medicine
TL;DR
This review synthesizes current understanding of the molecular and metabolic programs that stabilize tumor-associated Tregs and organizes them into an integrated framework linking antigen-driven activation, regulatory identity, metabolic adaptation, tissue-contextual reprogramming, and therapeutic resistance.
Abstract
Regulatory T cells (Tregs) are essential mediators of immune tolerance that maintain tissue homeostasis by restraining excessive immune activation. In cancer, these regulatory mechanisms are reinforced within malignant tissues and contribute to suppression of endogenous anti-tumor immunity. Tumor-infiltrating Tregs (TI-Tregs) represent a specialized activation state shaped by chronic antigen exposure, inflammatory cytokines, stromal cues, and metabolic stress imposed by the tumor microenvironment (TME). Rather than functioning as a static suppressive lineage, intratumoral Tregs integrate receptor-mediated signaling, FOXP3-centered transcriptional stabilization, and metabolic licensing, and spatial niche formation to maintain suppressive fitness under hypoxic and nutrient-restricted conditions. This review synthesizes current understanding of the molecular and metabolic programs that stabilize tumor-associated Tregs and organizes them into an integrated framework linking antigen-driven activation, regulatory identity, metabolic adaptation, tissue-contextual reprogramming, and therapeutic resistance. We further discuss emerging therapeutic strategies aimed at selectively modulating tumor-associated regulatory states while preserving systemic immune tolerance, with explicit attention to preclinical versus clinical evidence, tumor-type specificity, and toxicity risks.
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.
Yusuke Fukiage, Nodoka Okubo, M. Taga et al.· Frontiers in Molecular Biosc...· 0 citations
Regulatory T cells (Tregs) play a pivotal role in maintaining immune homeostasis by exerting precise control over immune activation, suppressing excessive responses, and facilitating tissue repair. These specialized CD4+ T cells, characterized by FOXP3 expression, function as key regulators that prevent pathogen-directed immune responses from progressing to deleterious autoimmunity or chronic inflammation. Tregs mediate suppression via secretion of cytokines such as IL-10 and TGF-β, metabolic disruption, and direct modulation of effector immune cells, thereby maintaining equilibrium between protective immunity and peripheral tolerance. Both thymically derived natural Tregs (nTregs) and peripherally induced Tregs (pTregs) exhibit phenotypic plasticity, adapting to diverse inflammatory milieus and tissue microenvironments through an array of suppressive mechanisms that orchestrate immune regulation and facilitate tissue repair. This functional heterogeneity manifests across lymphoid and non-lymphoid tissues, wherein Tregs dynamically adapt to distinct microenvironments to mount tailored responses to infection, tissue injury, and inflammatory insults. Conversely, Tregs may promote disease progression in malignancies and persistent infections by attenuating antitumor and antimicrobial immune effector responses. Treg activity is essential for averting autoimmune pathologies, tempering inflammatory cascades, and fostering tissue regeneration, thereby rendering them indispensable for upholding both systemic and tissue-specific immune homeostasis. Elucidation of Treg immunobiology unveils substantial therapeutic prospects across a diverse array of pathologies; targeted modulation of Treg frequency and functionality offers promise for ameliorating autoimmunity, mitigating transplant rejection, and combating malignancy. This narrative review delineates the multifaceted roles of Tregs in immune homeostasis, elucidates emerging insights into their mechanistic underpinnings, and evaluates prospective applications in next-generation immunotherapeutic interventions.
M. Salam, M. Al-Amin, Kasireddy Sudarshan et al.· Cells· 0 citations
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
Regulatory T cells (Tregs) maintain immune homeostasis, but in cancer the same FOXP3-dependent programme can be co-opted to protect malignant tissue from immune elimination. This review critically synthesizes spatially resolved, single-cell and mechanistic evidence to determine when tumour-associated Tregs constitute active components of suppressive multicellular niches rather than merely correlates of immune exclusion. We integrate tumour-adapted regulatory states with anatomical positioning, neighbouring malignant and non-malignant cells, candidate suppressive mechanisms and upstream tumour-intrinsic, stromal and myeloid programmes. This framework distinguishes Treg-dominant suppressive niches from Treg-associated architectures in which regulatory-cell accumulation is secondary to other resistance mechanisms. We examine tumour nests, invasive margins, dendritic-cell and lymphoid aggregates, stromal and perivascular barriers, and hypoxic or metabolically constrained regions, assessing the strength of evidence linking each context to local immune restraint. We further consider how these niches emerge during tumour progression, change under therapeutic pressure, and persist, relocate or re-form during resistance. We evaluate selective depletion strategies targeting CCR8, CD25 and CTLA-4, together with functional reprogramming of TGF-β, adenosine, kynurenine, lactate, hypoxia and IL-2 pathways. Finally, we propose a tiered biomarker framework integrating Treg phenotype, transcriptional state, spatiotemporal topology, functional immune competence and longitudinal pharmacodynamic validation. The contribution of this Review is therefore not the niche concept itself, but its Treg-centred mechanistic and translational operationalization for identifying tumour-specific regulatory dependencies while preserving systemic self-tolerance.
Jhommara Bautista, Miranda Di Capua Delgado, Juliana Viteri-Recalde et al.· Frontiers in Cell and Develo...· 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
Tumor microenvironment-resident immunosuppressive cells-comprising myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages-constitute primary obstacles to effective cancer immunotherapy. Advances in single-cell and spatial multi-omics have uncovered their substantial functional heterogeneity, tissue-adaptive reprogramming, and organ-specific architectures distinguishing primary tumors from metastatic lesions. Beyond canonical immune checkpoint pathways, non-canonical regulatory layers--including metabolic-immune crosstalk, epigenetic regulation, microbiome-mediated distant signaling, and therapy-induced adaptive remodeling-further reinforce treatment resistance. Based on these mechanistic insights, systematic synergistic strategies have been developed, such as multi-pathway checkpoint blockade, ADC-immunotherapy combinations, temporally and spatially optimized conventional therapies, and targeted agents that deplete or reprogram suppressive populations. Emerging biomarkers, repurposed pharmaceuticals, and pan-cancer therapeutic principles are refining patient stratification and combination regimens. This review offers a comprehensive framework for understanding and surmounting immunosuppressive barriers in cancer therapy.
Meng-Meng Liu, Yi-Chen Zhu, He-Miao Liang et al.· Frontiers in Immunology· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
