Regulatory T Cell Heterogeneity in the Steady State and Tumor.

Abstract

Tregs are essential for maintaining immune homeostasis and preventing autoimmunity. In the steady state, Tregs adopt distinct developmental, cytokine-dependent, and tissue-adapted programs that induce substantial heterogeneity across tissues. This diversity supports their context-dependent roles in maintaining barrier integrity, regulating inflammation, and supporting tissue repair. In the tumor microenvironment, Tregs are further differentiated in response to chronic antigen stimulation and local environmental cues, generating tumor-infiltrating Tregs with specialized suppressive functions. This review integrates insights from developmental pathways, tissue residency programs, transcriptional profiling, and tumor-specific adaptation, highlighting the current understanding of Treg heterogeneity in the steady state and tumor. Finally, we discuss therapeutic strategies designed to selectively target tumor-resident Tregs while preserving systemic immune tolerance.