High-throughput drug screening identifies SMAC mimetics as enhancers of NK-cell cytotoxicity in chronic myeloid leukemia

Natural killer (NK) cells have proven to be safe and effective immunotherapies, associated with favorable treatment responses in chronic myeloid leukemia (CML). Augmenting NK-cell function with oncological drugs could improve NK-cell–based immunotherapies. Here, we used a high-throughput drug screen consisting of >500 small-molecule compounds, to systematically evaluate the effects of oncological drugs on primary NK cells against CML cells. We identified second mitochondrially derived activator of caspases (SMAC) mimetics as potent enhancers of NK-cell cytotoxicity in both cell lines and primary patient samples. In contrast, several drug classes, including glucocorticoids and tyrosine kinase inhibitors such as dasatinib, inhibited NK-cell cytotoxicity. Single-cell RNA sequencing revealed drug-induced transcriptomic changes in both NK and target CML cells. SMAC mimetics upregulated NF-κB target genes in NK cells, potentially contributing to their enhanced cytotoxicity. Inhibitory drugs dexamethasone, dasatinib, and sotrastaurin prevented NK-cell transition to an activated state and suppressed the expression of interferon gamma (IFN-γ) by NK cells, thus preventing IFN-γ–mediated target cell transcriptomic response. In conclusion, we discovered that SMAC mimetics sensitize cancer cells to NK-cell–mediated killing, with potential clinical applications especially in patients with advanced phase CML.