PROGRAMMABLE IMMUNITY REDEFINED: A STANDARD REVIEW OF CAR-T CELL THERAPY BEYOND ONCOLOGY

Chimeric antigen receptor (CAR)-T cell therapy represents one of the most transformative advances in modern immunotherapy, achieving remarkable clinical success in relapsed and refractory hematological malignancies. Beyond oncology, rapid progress in genetic engineering, synthetic biology, and immune modulation has expanded CAR-T applications into autoimmune diseases, transplantation tolerance, infectious diseases, fibrotic disorders, and regenerative medicine. This review provides a comprehensive synthesis of contemporary evidence on CAR-T cell design evolution, mechanisms of action, clinical outcomes, and emerging translational frontiers. We discuss successive generations of CAR constructs, including armored, logic-gated, switchable, and regulatory CAR-T (CAR-Treg) platforms, highlighting their roles in enhancing specificity, persistence, and safety. Particular emphasis is placed on managing therapy-associated toxicities such as cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, alongside innovations in safety switches and controllable receptors. Manufacturing challenges, including scalability, cost, and regulatory complexity, are critically examined, with attention to allogeneic and off-the-shelf solutions. Finally, future perspectives explore the integration of artificial intelligence–guided antigen discovery, gene editing technologies, and personalized immune profiling to optimize therapeutic efficacy and accessibility. By consolidating advances across oncology and non-oncological indications, this review establishes CAR-T cell therapy as a versatile, programmable immune platform poised to redefine treatment paradigms across diverse disease domains. Keywords: CAR-T cell therapy; chimeric antigen receptor; immunotherapy; cytokine release syndrome; CAR-Treg; synthetic biology; autoimmune diseases; transplantation tolerance