FOXP3 Stability-Adaptation Paradox: Reshaping Treg-Based Therapies for Intestinal Diseases.

Regulatory T cells (Tregs) maintain intestinal immune homeostasis, but their therapeutic potential is constrained by a fundamental paradox: the same plasticity that enables tissue repair renders FOXP3 vulnerable to degradation in chronic inflammation. Mechanistically, microbial metabolites (short-chain fatty acids, bile acids) and retinoic acid stabilize FOXP3 and induce RORγt⁺/GATA3⁺ Treg specialization. In contrast, inflammatory cytokines and succinate accumulation drive ER stress and post-translational FOXP3 degradation, leading to lineage instability in inflammatory bowel disease, colorectal cancer, and celiac disease. Current Tregs-based therapies-adoptive transfer, low-dose IL-2, CAR-Tregs, and microbiota consortia-have demonstrated safety profiles yet exhibit limited efficacy due to this inherent instability. Next-generation strategies therefore focus on actively stabilizing FOXP3 (e.g., gut-restricted HDAC inhibitors) and engineering exhaustion-resistant CAR-Tregs. Three questions remain for clinical translation: how to preserve Treg stability without compromising anti-tumor immunity; which biomarkers (succinate, TSDR methylation, FOXP3Δ2/FL ratio) predict response; and whether logic-gated CAR-Tregs can overcome exhaustion. Addressing these challenges will enable the development of precision Treg immunotherapy for intestinal diseases.