Pluripotent stem cell-derived NK progenitor cell therapy prevents tumour occurrence and eradicates minimal residual disease

Abstract The lack of persistence and short-term efficacy presents a major challenge for CAR-NK cell therapy. Here, we addressed this issue by developing pluripotent stem cell-derived NK lineage-committed progenitor (iNKP) cell therapy. For the first time, we generated abundant iNKP cells via an organoid culture system. The iNKP cells, engineered to express CXCR4 and chimeric antigen receptors (CAR), efficiently migrated to the bone marrow and generated CAR-iNK cells persisting in peripheral blood (PB) for over 80 days. Notably, CAR-iNKP cell therapy durably protected animals from tumour occurrence. Furthermore, a single low-dose infusion of CAR-iNKP cells following conventional chemotherapy eradicated minimal residual disease (MRD), leading to long-term complete remission. Our findings present a novel strategy to overcome the limitations of traditional CAR-NK cell therapy and offer dural breakthroughs for the prevention of tumour occurrence and relapse. Competing Interest Statement The authors have declared no competing interest. Data availability The scRNA-seq data of UCB_resting NK cells, PSC-derived cells from day 16-20 organoids, and CD19CAR-R4iNK cells from PB, BM, Liver, Lung, and Spleen have been deposited in the Genome Sequence Archive public database (HRA008662). The scRNA-seq data of natural NKP and NK are from the Gene Expression Omnibus database (GSE149938). The accession number scRNA-seq data of UCB_activated NK is HRA007978. The accession number scRNA-seq data of PSC-iNK, PB_resting NK cells, and PB_activated cells is HRA001609.