Next-Generation CAR-T Therapies: From Personalized Anticancer Drugs to Broadly Applicable Disease-Modifying Treatments.

Chimeric Antigen Receptor T (CAR-T) cell therapy is evolving beyond traditional autologous products. Two transformative directions are emerging: Allogeneic CAR-T and In vivo CAR-T. Allogeneic CAR-T addresses immune incompatibility through both gene editing (e.g., TCR/HLA knockout) and nongene editing strategies (e.g., shRNA, protein expression blockers), overcoming graft-versus-host disease (GVHD) and host-versus-graft reaction (HvGR) to enable off-the-shelf production. In vivo CAR-T, leveraging engineered viral vectors and targeted lipid nanoparticles (tLNP), achieves in situ reprogramming of endogenous T cells, bypassing the need for ex vivo cell processing. These advancements are expanding CAR-T applications from hematological malignancies to autoimmune diseases (e.g., systemic lupus erythematosus, multiple sclerosis) and other conditions (e.g., fibrosis, HIV/AIDS). Despite challenges such as insufficient persistence of allogeneic CAR-T, imprecise delivery of In vivo CAR-T, safety concerns, ongoing advancements in targeted vectors, novel antigens, and combination therapies hold promise for enhancing efficacy and accessibility. This review summarizes the core strategies, clinical progress, cross-disease applications, and future directions, charting CAR-T's transition from a niche precision medicine toward a broadly applicable immunotherapy.