Gene transfer and genome editing of T cells for cancer immunotherapy: from allogeneic HSCT to TCR gene editing.

Adoptive T-cell therapy has emerged as a transformative modality in cancer immunotherapy, building upon foundational principles established in allogeneic hematopoietic stem cell transplantation. In this setting, while donor T cells mediate curative graft-versus-leukemia and graft-versus-infection effects, their alloreactivity poses significant risks. Gene transfer strategies-such as suicide gene insertion-have enabled the safer use of donor lymphocytes by allowing the selective elimination of T cells in case of adverse events. With this initial gene therapy approach, several lessons on the function, persistence, safety, and efficacy of engineered T cells were learned. More recently, advances in genome editing technologies have enabled precise manipulation of T-cell genomes and function, including disruption of endogenous T-cell receptors (TCRs) and insertion of tumor-specific receptors, such as chimeric antigen receptors and tumor-specific TCRs. Integration of T-cell manufacturing protocols optimized for persistence and resistance to immune suppression-largely facilitated by the possibility to simultaneously edit multiple genes (multiplex genome editing) in the same cells-has positioned engineered T cells as programmable and persistent therapeutics. Here, we briefly review key milestones, challenges, and innovations in T-cell gene engineering, from allogeneic hematopoietic stem cell transplantation to next-generation TCR-edited immunotherapies.