Tumor-adapted regulatory T cells: Molecular reprogramming, immune suppression, and therapeutic targeting in cancer.

Regulatory T cells (Tregs) are central to the maintenance of immune tolerance; however, in cancer they acquire a paradoxical role as key drivers of immune evasion and tumor progression. Within the tumor microenvironment (TME), Tregs undergo extensive phenotypic, transcriptional, and metabolic reprogramming that enhances their suppressive capacity and enables their persistence under conditions of hypoxia, nutrient limitation, and chronic inflammation. Tumor-infiltrating Tregs (TI-Tregs) display a distinct checkpoint-enriched phenotype, characterized by elevated expression of CTLA-4, PD-1, TIGIT, ICOS, and LAG-3, and are governed by integrated signaling networks involving FOXP3, IL-2/STAT5, and PI3K-AKT-mTOR pathways, coupled with specialized immunometabolism adaptations. In addition to classical signaling mechanisms, epigenetic regulation and non-coding RNAs (including microRNAs, long non-coding RNAs, and circular RNAs) play critical roles in shaping Treg stability, plasticity, and functional specialization within tumors. Emerging evidence further indicates that TI-Tregs operate within a complex immunoregulatory ecosystem, interacting with myeloid, stromal, and tumor cells to establish spatially organized and self-reinforcing networks of immune suppression. This review provides a comprehensive and integrative overview of the molecular mechanisms driving Treg reprogramming in cancer and examines the challenges associated with their therapeutic targeting. We highlight current and emerging strategies aimed at selectively disrupting tumor-specific Treg function, including checkpoint modulation, metabolic targeting, and subset-specific depletion. A deeper understanding of Treg heterogeneity, plasticity, and spatial organization will be essential for the development of next-generation precision immunotherapies capable of overcoming resistance while preserving systemic immune tolerance.