Engineering viral vectors for in vivo CAR-T generation: Advances, challenges, and opportunities

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematological malignancies but remains constrained by complex, individualized ex vivo manufacturing, limiting its accessibility and scalability. Direct in vivo generation of CAR-T cells within the patient offers a transformative approach to overcome these bottlenecks. However, the viral vector systems that enable this process have received comparatively limited attention in existing literature, where most reviews emphasize non-viral technologies. This review focuses on viral vectors as the pivotal enablers of in vivo CAR-T therapy. We summarize major directions in vector innovation, including engineering strategies to enhance tropism and safety, clinical applications across diverse disease settings, and the intrinsic trade-offs that shape translational outcomes. Current challenges are considered in the context of emerging technologies designed to improve precision, controllability, and clinical feasibility. By integrating these perspectives, this review outlines how viral vector-mediated in vivo CAR-T platforms may evolve toward more accessible, programmable, and safer next-generation cell therapies.