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Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced antitumor function after stimulation with interleukin-12 (IL-12), IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA-haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on day +7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in a clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well tolerated, and 87% of patients achieved a composite complete response at day +28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for 2 months after HCT with 1104-fold expansion (over 1 to 2 weeks). Phenotypic and transcriptional analyses identified donor ML NK cells as distinct from conventional NK cells and showed that ML NK cells persisted for over 2 months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patients and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML. Naturally killing leukemia: Natural killer (NK) cells are innate immune cells that are under investigation as a cell therapy for multiple types of cancer. A challenge for NK cell–based therapies, however, is ensuring that the cells persist and remain functional long-term. Here, Berrien-Elliott et al. generated cytokine-induced memory-like NK (ML NK) cells as a therapeutic for leukemia and investigated their functional capacity and persistence in patients receiving HLA-haploidentical hematopoietic cell transplantation (HCT). The authors showed that ML NK cells derived from the same donor as the HCT persisted for at least 2 months after HCT and were highly functional ex vivo. Together, these findings support the use of ML NK cells as a component of HCT for leukemia. [ABSTRACT FROM AUTHOR]