Pluripotent stem cell-derived CAR-NK progenitor therapy targets minimal residual disease and prevents relapse in leukemia models.

Reducing relapse rates post-chemotherapy remains a major challenge for improving cancer therapy. Here, we developed a pluripotent stem cell-derived induced natural killer (NK) lineage-committed progenitor (iNKP) cell therapy in leukemia models. We generated abundant iNKP cells via an organoid culture system. The iNKP cells, engineered to express C-X-C motif chemokine receptor 4 (CXCR4) and chimeric antigen receptors (CARs), efficiently migrated to the bone marrow and generated CAR-iNK cells, which persisted in multiple organs and peripheral blood for over 80 days. Notably, CAR-iNKP cell infusion precisely protected animals from tumor challenges. Furthermore, a single low-dose infusion of CAR-iNKP cells following conventional chemotherapy reduced minimal residual disease and significantly prevented cancer relapse in human CD19 B-ALL and CD7 T-ALL tumor-bearing animals. CAR-iNKP cell treatment addresses the limitations of traditional CAR-NK cell infusion and offers a new strategy for future application in human cancer therapy.