The landscape of genetic medicines for in vivo T cell reprogramming

In vivo reprogramming of T cells represents a transformative approach in immune-based therapies, with the potential to overcome the limitations of traditional ex vivo-engineered T cell products, such as autologous CAR-T therapies. While CAR-T cells have achieved remarkable success in treating hematological cancers with several FDA-approved products, challenges like manufacturing complexity, costs, toxicity, and relapse rates persist. In this review, we first provide a brief background on T cell biology and CAR T cells, and then present a comprehensive overview of emerging strategies for direct in vivo T cell reprogramming. We discuss the key platform technologies, including lipid nanoparticles and viral vectors, and the targeting methods employed to enhance delivery and efficacy. Moreover, we evaluate the functional state of reprogrammed T cells and the role of different mouse models and reporter systems in assessing their therapeutic potential. We highlight key challenges related to the biodistribution, activation, and persistence of modified T cells, with an emphasis on the potential of these strategies for treating not only blood cancers but also solid tumors, autoimmune diseases, and beyond. Finally, we provide an outlook on future directions by highlighting recent non-human primate studies, ongoing clinical activities, and strategic acquisitions representing key innovations, and discuss remaining translational hurdles in the field.