Antigen-specific tolerance therapies in type 1 diabetes: Disease-specific promises meet stage-specific challenges

Type 1 diabetes (T1D) is a progressive autoimmune disease characterized by immune-mediated β-cell destruction, evolving from genetic susceptibility (stage 0) to presymptomatic autoimmunity (stages 1-2) and clinically symptomatic disease (stages 3-4). Immune activation becomes increasingly pronounced throughout disease progression, highlighting a window for timely intervention to preserve residual β-cell function. Current disease-modifying therapies primarily target broad immune pathways or cell populations, such as T-cell activation and regulation. While these approaches can transiently preserve β-cell function, they lack antigen specificity, show limited durability, and may carry risks of systemic immunosuppression. Antigen-specific immunotherapy (ASI) aims to restore immune tolerance to disease-relevant antigens while maintaining overall immune competence. As pathogenic mechanisms and dominant antigenic targets evolve throughout T1D progression, ASI strategies will require stage-specific application. Moreover, genetic variation, including HLA haplotypes and insulin gene polymorphisms, shapes antigen-specific immune responses and supports patient stratification in ASI design. Early ASI approaches focused on peptide- and protein-based antigen formulations, whereas newer platforms include nucleic acid-based vaccines enabling controlled antigen expression and tolerogenic presentation. Engineered microbial delivery systems, such as Lactococcus lactis, offer targeted mucosal delivery of antigens and immunomodulators to promote localized tolerance. In parallel, adoptive cellular therapies, including regulatory T cells (Tregs) and chimeric antigen receptor (CAR) Tregs engineered to recognize β-cell antigens, represent a promising strategy to restore antigen-specific immune regulation within inflamed islets. Advanced biomaterial carriers further enhance targeted delivery and controlled antigen release. Despite its strong rationale, ASI has shown limited success in clinical trials, highlighting challenges in achieving durable immune tolerance. This may in part reflect heterogeneity in disease stage, genetic background, and underlying immune pathways, underscoring the need for biomarker-guided patient stratification. Combination approaches integrating ASI with complementary immunomodulatory strategies may therefore be required to achieve stable, antigen-specific tolerance and effectively modify disease progression.