In vivo CAR-T therapy: latest updates from the 2025 ASH annual meeting.

Chimeric antigen receptor (CAR)-T cell therapy has significantly improved outcomes in hematologic malignancies but remains constrained by complex ex vivo manufacturing and lymphodepleting chemotherapy. In vivo CAR-T therapy enables direct genetic programming of endogenous T cells through systemic delivery of CAR-encoding vectors, thereby bypassing ex vivo manipulation and simplifying treatment workflows. This strategy has the potential to reduce production timelines, lower costs, and broaden patient accessibility. In addition, in vivo CAR-T approaches may preserve more physiological T-cell states and offer improved scalability. Importantly, however, current in vivo CAR-T platforms differ substantially in delivery modality, persistence, reversibility, safety profile, and translational feasibility. Here, we summarize the latest advances in major preclinical approaches and early clinical studies presented at the 2025 ASH annual meeting, with emphasis on the comparative strengths, limitations, and translational trade-offs of viral vector-based, RNA/lipid nanoparticle-based, non-viral DNA, and gene-writing strategies.