Transcriptional changes in human natural killer cells derived from umbilical cord blood in response to the BCL-2 inhibitor Venetoclax
Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment, but its efficacy is still limited, necessitating the development of new strategies. Here, we report an unexpected discovery that venetoclax, the first FDA-approved BCL-2 inhibitor, acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against acute myeloid leukemia (AML). Venetoclax directly activates human NK cells, boosting their cytotoxicity against AML both in vitro and in vivo, independent of BCL-2 inhibition. Venetoclax enhances NK cell binding avidity and lytic granule polarization during immunological synapse (IS) formation.Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-?B pathway, facilitating IS formation and effector function in human NK cells.Our findings establish venetoclax as a multifaceted immunometabolic modulator that enhances NK cell function, providing new insights for augmenting NK cell-mediated cytotoxicity in cancer immunotherapy. Overall design: In order to explore the regulatory role of Venetoclax in the killing function of NK cells, we isolated and purified NK cells derived from umbilical cord blood and treated them with Venetoclax for 18 hours.We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different donors .Comparative gene expression profling analysis of RNA-seq data for freshly isolated NK cell  treat with or without Venetoclax.