Th1-Adapted Regulatory T Cells in Tumor Immunity and Inflammatory Diseases.

Abstract

Regulatory T cells (Tregs) play an essential role in maintaining immune tolerance and controlling excessive inflammation. Although traditionally viewed as a stable lineage dedicated to broad immunosuppression, accumulating evidence has revealed that Tregs exhibit remarkable heterogeneity and functional adaptability, allowing them to undergo specialization in response to local inflammatory environments. Among these specialized subsets, Th1-type Tregs (Th1-Tregs), characterized by the co-expression of Foxp3 and the transcription factor T-bet, have emerged as key regulators of type 1 immune responses. By expressing the chemokine receptor CXCR3, these cells localize to IFN-γ-rich inflammatory sites and selectively modulate Th1-driven immune circuits. Recent studies have demonstrated that Th1-Tregs play context-dependent roles across diverse pathological conditions. In the tumor microenvironment, they suppress cytotoxic immunity and contribute to tumor immune evasion. In contrast, during autoimmune diseases and acute infections, Th1-adapted regulatory programs protect host tissues by restraining excessive inflammation. These findings highlight how regulatory T cells dynamically adapt to local inflammatory environments to control type 1 immune responses in different tissues. In this review, we summarize the molecular mechanisms underlying Th1-Treg differentiation and discuss how these specialized regulatory programs shape immune responses across different disease contexts.