Regulatory T cells in the tumor microenvironment: Mechanisms and clinical implications

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.