Application and Challenges of Chimeric Antigen Receptor T Cell Therapy in Systemic Rheumatic Diseases and Autoimmune Disorders

ABSTRACT Chimeric antigen receptor T (CAR‐T) cell therapy, originally developed for hematologic malignancies, has emerged as a transformative candidate for systemic rheumatic diseases and autoimmune disorders (AIDs). Its unique efficacy in refractory AIDs relies on depleting autoreactive B cells and driving antigen‐naïve immune reconstitution, achieving durable drug‐free remission in early‐phase trials. Despite promising clinical and serological responses lasting 2–5 years without long‐term immunosuppression, the field faces unmet needs: complex manufacturing, limited tissue penetration, antigen escape, immunological sequelae, and lack of predictive biomarkers. Existing reviews predominantly focus on oncology adaptations or isolated technical aspects, lacking systematic integration of mechanisms, challenges, and precision‐oriented innovations for rheumatic diseases. This review comprehensively summarizes CAR‐T's action mechanisms in AIDs, analyzes core clinical challenges, and highlights emerging strategies—including universal/in vivo‐generated CAR‐T cells, multitargeted/logic‐gated designs, organ‐homing engineering, and rational combinations with tolerance‐enhancing agents. It further emphasizes multiomics integration (single‐cell transcriptomics, spatial mapping, B‐cell receptor/T‐cell receptor repertoire analysis) for patient stratification and relapse prediction. By bridging mechanism‐driven engineering with clinical translation, this work provides an actionable framework to advance CAR‐T toward functional immune reset, enabling precision immunotherapy for refractory rheumatic diseases and AIDs.