Emerging CAR immunotherapies: broadening therapeutic horizons beyond cancer

Chimeric antigen receptor-based immunotherapy has transformed cancer treatment, especially for hematologic malignancies like acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Innovations in CAR design from first-generation constructs relying on CD3ζ signaling to next-generation CARs with co-stimulatory domains have enhanced T cell persistence and antitumor efficacy. Despite these successes, translating CAR-T therapy to solid tumors faces significant challenges, including antigen heterogeneity, immunosuppressive tumor microenvironments, and toxicities such as cytokine release syndrome and neurotoxicity. To overcome these hurdles, CAR therapies involving alternative immune cells are currently being developed, such as CAR-natural killer, CAR-T regulatory (Treg), CAR-macrophages (Ms), and others, each offering distinct biological advantages and potential for broader applications. Beyond oncology, CAR approaches are being explored for autoimmune diseases, infectious diseases, and fibrosis, expanding their therapeutic scope. Manufacturing complexities and safety concerns related to gene modification also highlight the need for scalable, safe production methods, including non-viral gene delivery systems. This review summarizes the evolution, current applications, and future prospects of CAR-based therapies, emphasizing the importance of ongoing innovation to enhance specificity, safety, and clinical efficacy across diverse disease contexts.