Beyond Foxp3 and TSDR: a dual epigenetic lock framework for treg stability and plasticity.

Regulatory T cells (Tregs) maintain immune homeostasis by balancing lineage stability with functional adaptability. Although Foxp3 is central to Treg identity, Foxp3 expression alone does not fully explain the long-term maintenance of suppressive function or the capacity of Tregs to adapt to diverse tissue environments. Similarly, Foxp3 TSDR demethylation provides a durable epigenetic imprint but does not account for the dynamic regulation of broader Treg functional programs. Here, we propose the Dual Epigenetic Lock framework as a conceptual and testable model in which two complementary epigenetic layers contribute to Treg state regulation. The first lock consists of stable TSDR demethylation, which preserves lineage-associated Foxp3 expression competence. The second lock is proposed to involve Treg-associated super-enhancer networks that may stabilize suppressive transcriptional programs, regulate environmental adaptation, and constrain inappropriate inflammatory activation. This framework suggests that Treg stability emerges from the integration of durable lineage memory and dynamic functional regulation rather than from a single molecular determinant. Disruption of this balance may contribute to impaired immune tolerance in autoimmune diseases, whereas excessive reinforcement of suppressive regulatory programs may support tumor immune evasion. However, the extent to which these two epigenetic layers are mechanistically coupled remains unresolved. Emerging approaches including single-cell multi-omics, spatial epigenomics, and targeted epigenome engineering provide opportunities to test whether the dual-lock architecture predicts Treg state transitions and therapeutic responsiveness. This framework also provides a conceptual basis for two complementary therapeutic strategies: reinforcing Treg stability for immune tolerance and selectively modulating tumor-associated Treg programs for cancer immunotherapy.