Stage-Adapted Disease-Modifying Therapy in Type 1 Diabetes.

AIMS: To propose a stage-adapted framework for disease-modifying therapy in type 1 diabetes (T1D) that integrates immune plasticity and residual β-cell function, and to examine how these evolving constraints may inform treatment selection, combination strategies, and trial endpoints. MATERIALS AND METHODS: This narrative review synthesizes mechanistic, observational, and interventional evidence across presymptomatic T1D, recent-onset Stage 3 disease, and longer-duration Stage 3 disease. Evidence relating to immune modulation, antigen-specific intervention, β-cell protection, and β-cell replacement was interpreted according to disease stage and biological context. RESULTS: Available evidence suggests that therapeutic responsiveness is shaped by two co-evolving constraints: immune plasticity and residual β-cell function. Early disease may provide a window in which autoreactive immunity can still be redirected and endogenous β-cell function preserved. In established disease, stabilized immune memory, reduced regulatory capacity, and substantial β-cell loss increasingly limit the effects of immune-directed intervention alone. Accordingly, immune-tolerance and β-cell-preservation strategies may have greater potential earlier in the disease course, whereas established disease may require β-cell replacement combined with graft protection and metabolic management. CONCLUSIONS: Stage-adapted treatment matching provides a clinically interpretable framework rather than a validated treatment algorithm. Integrating disease stage with immune endotype, residual β-cell function, treatment feasibility, and stage-appropriate endpoints may improve the design and interpretation of disease-modifying trials and warrants prospective validation.