Immune Mechanisms and Translational Therapeutic Challenges in Type 1 Diabetes

ABSTRACT Aims Type 1 diabetes mellitus (T1DM) is an autoimmune disease driven by genetic susceptibility and triggered by environmental cues. This review aims to systematically elaborate the full pathogenic cascade of T1DM involving the crosstalk among genetics, environment, immunity and pancreatic target cells, and summarize current preventive and therapeutic strategies together with outstanding unresolved questions. Materials and Methods We reviewed published literatures regarding T1DM pathogenesis, preclinical intervention and curative β cell replacement therapy, focusing on established immune mechanisms, controversial hypotheses and translational barriers. Results Breakdown of immune tolerance leads to progressive destruction of pancreatic β cells mediated by autoreactive CD4 + and CD8 + T cells, resulting in absolute insulin deficiency and lifelong exogenous insulin dependence. Viral infection serves as a major disease trigger, while multiple pathways including β cell stress‐related neoantigen formation, gut microbiota‐intestinal barrier dysfunction, mechanosensing‐dependent immune cell homing and epigenetic modification of memory T cells jointly drive disease progression. T1DM follows a 1–3 staging framework, providing an intervention window at preclinical stages. Current therapies can merely delay onset, and stem‐cell‐derived β cell transplantation is restricted by allogeneic rejection and recurrent autoimmunity. Conclusions Multiple intertwined genetic‐environmental‐immune events initiate and propagate T1DM. Novel strategies targeting key pathogenic nodes are urgently required to eliminate autoimmune memory, and further translational studies are needed to achieve curative treatment for T1DM.