Chronic inflammation deters natural killer cell fitness and cytotoxicity in myeloid leukemia

•Our study identifies the susceptibility of NK cells to the leukemic inflammatory environment.•CML milieu hinders NK cell cytotoxicity, highlighting the therapeutic potential of targeting proinflammatory cytokine signaling to enhance leukemic immunosurveillance.•BCR::ABL1– NK cells in a chimeric mouse model of CML correlate with NK cells from patients with high-risk CML and acquire TNFα-induced proinflammatory gene signature. [Display omitted] Natural killer (NK) cells play an integral role in immunosurveillance against myeloid malignancies, with their mature phenotype and abundance linked to prolonged treatment-free remission in chronic myeloid leukemia (CML). However, NK cell function is suppressed during the disease, and the orchestrators of this impairment are not fully understood. Using a chimeric BCR::ABL1+ CML mouse model, we characterized the impact of the leukemic microenvironment on NK cell function. We showed that NK cells have reduced counts, immature phenotype, poor cytotoxicity, and altered expression of activating and inhibitory receptors in CML mice, which revert to a steady state upon BCR::ABL1 inhibition. Single-cell RNA sequencing revealed an inflammatory cytokine response in CML-exposed NK cells, highlighted by the tumor necrosis factor α (TNFα)-induced gene signature, upregulation of TNFα receptor 2, and enrichment of SOCS family genes such as Cish, the critical NK cell checkpoint. Ex vivo exposure of healthy NK cells to leukemic soluble factors compromised target-specific NK cell degranulation, which was partially rescued by targeting Cish or TNFα. In alignment with these findings, NK cells from healthy donors displayed suppressed cytotoxicity when exposed to plasma from untreated patients with CML, with a partial restoration upon Cish or TNFα inhibition. Furthermore, NK cells from newly diagnosed patients with CML predestined for blast crisis showed an enrichment of the TNFα-induced proinflammatory gene signature identified in CML mice. These results suggest that targeting inflammatory signaling could enhance NK cell-based immunotherapies for CML.