Improvement of Treg Selectivity and Stability for Diabetes Mellitus Type 1 Treatment: Complex Approach for Perspective Technologies

Highlights: What are the main findings? The efficacy of CAR-Treg therapies for type 1 diabetes is potentially limited by the instability of their phenotype in the inflammatory microenvironment caused by proinflammatory immune cells. Recent studies in immunology and translational medicine are aimed at Treg phe-notype stabilization. What are the implications of the main findings? A complex approach based on different methods such as the genetic engineering of cytokine signaling pathways and the cAMP cascade, the management of FOXP3 splicing to ensure stable expression of a certain splice variant, and the use of some epigenetic modifications can be applied for effective Treg stabilization. A synergistic strategy based on CAR and stabilizing modifications of autologous Tregs with their subsequent transplantation is promising for type 1 diabetes therapy. The adoptive transfer of Tregs is a promising immunotherapeutic strategy for type 1 diabetes mellitus (T1D). A key focus in this field is the creation of antigen-specific CAR-Tregs targeted against pancreatic islet antigens. However, the efficacy of such therapies is potentially limited by the instability of the Treg phenotype in the inflammatory conditions of T1D. This review discusses molecular approaches to overcome this limitation. These include the genetic engineering of cytokine signaling pathways (IL2, IL33/ST2, and IL35) and the cAMP cascade, the management of FOXP3 splicing to ensure stable expression of concrete splice variants, and the use of epigenetic mechanisms to promote a durable Treg identity. © 2025 by the authors.