Reprogramming immunity: Emerging therapeutic frontiers and clinical trial advances of CAR-T cell therapy in autoimmune diseases

Abstract

Autoimmune diseases result from a breakdown in immune tolerance, leading to chronic activation of autoreactive lymphocytes. Conventional therapies offer symptomatic relief but rarely achieve durable remission. Chimeric antigen receptor (CAR)-T cell therapy, originally developed for hematologic malignancies, is now being repurposed to selectively deplete pathogenic immune subsets in autoimmunity. This review explores how CAR-T cells may not only eliminate autoreactive B and T cells but also reprogram immune homeostasis toward long-term tolerance. Recent clinical success with CD19-directed CAR-T cells in refractory systemic lupus erythematosus underscores this paradigm shift. Furthermore, next-generation constructs including dual CARs, inhibitory CARs (iCARs), and CAR-Tregs offer innovative strategies to balance cytotoxicity with regulatory control. Key challenges such as antigen escape, off-target effects, and therapeutic accessibility are critically analyzed within current translational and clinical landscapes. This work advocates for a mechanistically guided redefinition of autoimmune therapy through precision-engineered immune reprogramming.