Glucose is an important fuel for NK cell metabolism and cytotoxic function but is often depleted in the tumor microenvironment (TME). Fatty acids (FAs), on the other hand, have been found to be more abundant and could therefore serve as a valuable fuel source for the metabolic requirements of NK cell cytotoxicity through fatty acid oxidation (FAO). DnaJ heat shock protein family (Hsp40) member C15 (DnaJC15), a negative regulator of Complex I in the electron transport chain, has recently been identified as a target to increase mitochondrial metabolism and enhance efficacy of adoptive T cell therapies. Single-cell RNA sequencing revealed selective upregulation of several critical components for driving FAO and mitochondrial respiration, including DnaJC15, CPT1A, ACLY, and SLC25A1, in IL-15 stimulated primary NK cells, expanded adaptive NK cells and in iPSC-derived NK cells. CRISPR/Cas9-mediated deletion of DnaJC15 in primary NK cells did not impair viability, IFNg production, or NK cell activation in response to target cell stimulation. Furthermore, metabolism profiling using SCENITH demonstrated intact cellular metabolism at steady state. We hypothesize that DnaJC15 deletion may result in increased FAO and functionality of NK cells under FA-enriched culture conditions, and experiments to investigate this are currently being conducted. These results will give further insight on whether deletion of DnaJC15 could render NK cells more metabolically robust in the FA-rich TME and the potential of this engineering strategy to improve NK cell immunotherapies for the treatment for solid cancers.