In vivo CAR‑T cell therapy: mechanisms, clinical advances and optimization strategies

In vivo CAR-T cell therapy is an innovative strategy that directly delivers CAR-encoding transgenes to endogenous T cells, reprogramming them in situ. It offers advantages of streamlined production and reduced costs. Published clinical trials have shown encouraging therapeutic outcomes for in vivo CAR-T. Nevertheless, multiple key obstacles still remain to be addressed. These obstacles include insufficient targeting specificity of delivery vehicles, vector-mediated immune clearance, manufacturing bottlenecks and safety concerns. The delivery system is a critical component of in vivo CAR-T therapy and can be classified into viral and non-viral vectors. Currently, optimizing delivery systems to support their robust implementation in preparation for in vivo CAR-T has become a critical factor in advancing in vivo CAR-T therapy. In this review, we first summarize the mechanisms, current clinical landscape, and major challenges of in vivo CAR-T cell therapy. Subsequently, in response to these challenges, we systematically outline existing optimization strategies applicable to this therapy. Additionally, we provide perspectives for researchers on the optimization of in vivo CAR-T cell therapy.