Unraveling the Epigenetic Regulation of Regulatory T Cells in Cancer Immunity

Regulatory T cells (Tregs) are central mediators of immune tolerance, yet within tumors they adopt specialized phenotypes that confer the potent suppression of anti-tumor immune responses. Emerging evidence indicates that this functional plasticity is not driven by genetic alterations but instead arises from dynamic and context-dependent epigenetic reprogramming. While individual epigenetic mechanisms controlling Treg development and stability have been described, how tumor-derived cues reshape Treg epigenetic states, how these programs differ across cancer types, and which features distinguish tumor-infiltrating Tregs from their peripheral counterparts remain incompletely understood. In this review, we synthesize recent advances in DNA methylation, histone modifications, chromatin accessibility, and non-coding RNA regulation that govern Treg identity and function with a particular emphasis on tumor-specific epigenetic adaptations. We highlight emerging epigenetic hallmarks of intratumoral Tregs, discuss unresolved mechanistic questions, and evaluate the therapeutic potential and limitations of targeting epigenetic pathways to selectively modulate Tregs in cancer. By integrating mechanistic, cancer-specific, and translational perspectives, this review aims to provide a conceptual framework for understanding how epigenetic regulation shapes Treg behavior in the tumor microenvironment and how it may be exploited for cancer immunotherapy.