The evolution of CAR therapies across oncology and autoimmunity: mechanistic insights and therapeutic innovations.

Chimeric antigen receptor (CAR)-engineered cellular therapies have progressed from early proof of concept into highly programmable platforms capable of mediating potent cytotoxicity and precise immune modulation. In oncology, successive CAR design has incorporated optimized costimulatory domains, cytokine-secreting modules, and gene-editing technologies to enhance efficacy and durability in hematologic malignancies. CD19- and BCMA-directed CAR-T cells induce deep and durable remissions in refractory B-cell leukemias, lymphomas, and multiple myeloma. Emerging strategies, including logic-gated CARs, synthetic Notch (SynNotch) circuits, and modular adaptor-based systems, aim to overcome antigen escape, reduce off-tumor toxicity, and extend efficacy to heterogeneous solid tumors. Concurrently, a conceptual shift has expanded CAR applications beyond cancer toward immune modulation in autoimmune diseases. CD19-directed CAR-T therapy has achieved deep B-cell depletion and clinical improvement in small early-phase studies (typically 5-18 patients) of systemic lupus erythematosus, inducing drug-free remission in some patients; however, randomized controlled trials are lacking and evidence remains preliminary. Antigen-specific approaches, including chimeric autoantibody receptor (CAAR)-T cells and CAR-engineered regulatory T-cells (CAR-Tregs), enable selective depletion of autoreactive B-cell clones or localized restoration of immune tolerance. These strategies are under investigation across systemic sclerosis, multiple sclerosis, myasthenia gravis, type 1 diabetes, inflammatory bowel disease, and rheumatoid arthritis. Collectively, advances in synthetic receptor engineering and translational application position CAR platforms as versatile, next-generation therapeutics across malignant and immune-mediated diseases.