Select subsets of immune effector cells have the greatest propensity to mediate antitumor responses. However, procuring these subsets is challenging, and cell-based immunotherapy is hampered by limited effector-cell persistence and lack of on-demand availability. To address these limitations, we generated a triple-gene-edited induced pluripotent stem cell (iPSC). The clonal iPSC line was engineered to express a high affinity, non-cleavable version of the Fc receptor CD16a and a membrane-bound interleukin (IL)-15/IL-15R fusion protein. The third edit was a knockout of the ecto-enzyme CD38, which hydrolyzes NAD+. Natural killer (NK) cells derived from these uniformly engineered iPSCs, termed iADAPT, displayed metabolic features and gene expression profiles mirroring those of cytomegalovirus-induced adaptive NK cells. iADAPT NK cells persisted in vivo in the absence of exogenous cytokine and elicited superior antitumor activity. Our findings suggest that unique subsets of the immune system can be modeled through iPSC technology for effective treatment of patients with advanced cancer. Display omitted •iADAPT NK cells and adaptive NK cells share metabolic and transcriptional features•iADAPT NK cells are cytokine autonomous•iADAPT NK cells display enhanced innate immune function Optimized iPSC-derived NK (iNK) cells have been developed for on-demand cancer immunotherapy. Here, Cichocki and colleagues describe a triple-gene-edited iNK cell product, termed iADAPT NK, which persists and functions in vivo in the absence of exogenous cytokines and can be combined with therapeutic antibodies for enhanced tumor targeting.