Unraveling the Epigenetic Regulation of Regulatory T Cells in Cancer Immunity

TL;DR

This review explores how epigenetic changes in regulatory T cells influence their role in suppressing anti-tumor immunity and how this could be targeted for cancer treatment.

Contribution

The paper provides a comprehensive synthesis of tumor-specific epigenetic adaptations in regulatory T cells and their implications for immunotherapy.

Findings

Tumor-derived cues dynamically reprogram regulatory T cell epigenetic states.

Epigenetic mechanisms like DNA methylation and chromatin accessibility shape Treg identity in cancer.

Targeting these pathways offers potential for selective modulation of Tregs in immunotherapy.

Abstract

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.

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