CAR T cell therapy beyond cancer: current status, challenges and future prospects

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized oncology, and its foundational logic-precise antigen recognition coupled with durable effector activity-extends naturally to chronic non-malignant diseases sustained by long-lived pathological cells. These include viral reservoirs, autoreactive B and plasma cells, activated fibroblasts, alloimmune clones, and senescent cells that remodel tissue niches and evade clearance by conventional therapies. This review highlights how CAR-based strategies can be adapted across diverse disease settings by redirecting engineered immune responses toward disease-sustaining cellular compartments. Co-stimulatory domains such as CD28, 4-1BB, and OX40 enhance persistence and effector function; programmed cell death protein 1 (PD-1)-CD28 switch receptors reverse inhibitory signaling; and cytokine-resistant CARs incorporating dominant-negative transforming growth factor-β (TGF-β) receptors maintain activity within suppressive microenvironments. We discuss these approaches across infections, including human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV); autoimmunity involving CD19- and B-cell maturation antigen (BCMA)-directed depletion strategies and CAR-engineered regulatory T cells (CAR-Tregs); fibrosis targeting fibroblast activation protein (FAP); hemophilia using B-cell antibody receptor (BAR)-CARs against factor VIII and factor IX inhibitors; transplantation employing human leukocyte antigen (HLA)-specific CAR-Tregs; and senescence-associated pathologies targeting urokinase plasminogen activator receptor (uPAR) and natural killer group 2D ligands (NKG2DLs). Early clinical experiences in systemic lupus erythematosus, systemic sclerosis, myositis, and multiple sclerosis, together with preclinical successes in chronic infections and fibrotic disease, demonstrate both feasibility and durable disease modification. By extending CAR-T therapy beyond oncology, these applications position programmable cellular immunotherapy as a broadly adaptable platform for eliminating persistent pathological cells, remodeling diseased tissue environments, and restoring long-term immune homeostasis.