Abstract
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β-cells in the pancreas. Regulatory T cells (Tregs) are essential for maintaining immune tolerance, but they manifest impaired functionality, particularly within the pancreatic microenvironment, during T1D development. This review aimed to discuss Treg biology including the developmental trajectory, phenotypic heterogeneity, and suppressive function, by which we sought to emphasize their compromised role in T1D pathogenesis associated with genetic/epigenetic factors along with impaired cytokine signaling. The unique chemokine receptor expression signature, migratory capacity, and metabolic adaptation of pancreatic Tregs are highlighted, alongside insights from single-cell studies. The evolution of Treg-based immunotherapies is explored, with emphasis on genetically engineered Tregs (EngTregs), which are designed for the stable ectopic expression of FoxP3 and antigen-specific receptors, such as T cell receptors (TCR) or chimeric antigen receptors (CAR). It also highlights advancements in genome-editing and delivery technologies, along with rationally designed combination strategies incorporated into multifunctional cellular products. Despite encouraging preclinical results, significant challenges persist in clinical translation. Overall, this review synthesizes existing knowledge and outlines future directions in Treg biology and immunotherapy, underscoring the potential of next-generation Treg therapy to achieve durable immune tolerance in T1D.