KDM4C inhibition reinforces NK cell cytotoxicity through the cGAS-STING pathway in TP53-mutated AML.
TP53-mutated acute myeloid leukemia (AML) is associated with an extremely poor prognosis and is refractory to conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). We identified high expression of lysine demethylase 4C (KDM4C) in AML, particularly in TP53-mutated AML. Pharmacological inhibition of KDM4C with QC6352 predominantly induced apoptosis in TP53-wild-type AML cells, whereas it caused limited apoptosis but pronounced senescence and growth arrest in TP53-mutated AML cells. In TP53-mutated AML cells, QC6352 induced senescence-associated cytosolic DNA accumulation and activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, leading to the upregulation of NK cell-activating ligands and enhancing NK cell-mediated cytotoxicity. In vivo, QC6352 effectively attenuated AML progression, and its combination with NK cell therapy further reduced leukemic burden and prolonged survival in mice. Collectively, these findings demonstrate that pharmacological KDM4C inhibition with QC6352 induces cellular senescence and enhances the intrinsic immunogenicity of TP53-mutated AML cells through activation of the cGAS-STING pathway. The study supports KDM4C inhibition as a potential therapeutic strategy for TP53-mutated AML, particularly in patients receiving NK cell-based immunotherapy or undergoing allo-HSCT.