A study identifies KDM6A as a key regulator of CD38 and CD48 expression in multiple myeloma (MM) cells, which influences the sensitivity of these cells to Daratumumab (Dara)-mediated antibody-dependent cellular cytotoxicity (ADCC). KDM6A, a histone demethylase, reduces H3K27me3 levels, leading to the upregulation of CD38 and CD48, which are essential for NK cell activity and Dara binding. Loss of KDM6A results in decreased CD38 and CD48 expression, reducing NK cell activity and increasing resistance to Dara. Reintroducing CD38 or CD48 partially restores sensitivity, suggesting that other KDM6A targets also contribute to ADCC. Inhibiting H3K27me3 with an EZH2 inhibitor increases CD38 and CD48 expression, restoring sensitivity to Dara. These findings suggest that KDM6A loss is a mechanism of Dara resistance in MM, and EZH2 inhibitors could improve MM responsiveness to Dara. The study also shows that KDM6A regulates CD48 expression, which is crucial for NK cell activation. CD48 loss reduces NK cell activity, leading to ADCC resistance. Overexpression of CD48 in KDM6A-KO cells restores ADCC sensitivity. EZH2 inhibitors increase CD38 and CD48 expression, enhancing Dara-mediated ADCC. The study highlights the role of KDM6A in epigenetic regulation of NK cell activity and provides a preclinical rationale for using EZH2 inhibitors in combination with Dara to overcome resistance in MM.A study identifies KDM6A as a key regulator of CD38 and CD48 expression in multiple myeloma (MM) cells, which influences the sensitivity of these cells to Daratumumab (Dara)-mediated antibody-dependent cellular cytotoxicity (ADCC). KDM6A, a histone demethylase, reduces H3K27me3 levels, leading to the upregulation of CD38 and CD48, which are essential for NK cell activity and Dara binding. Loss of KDM6A results in decreased CD38 and CD48 expression, reducing NK cell activity and increasing resistance to Dara. Reintroducing CD38 or CD48 partially restores sensitivity, suggesting that other KDM6A targets also contribute to ADCC. Inhibiting H3K27me3 with an EZH2 inhibitor increases CD38 and CD48 expression, restoring sensitivity to Dara. These findings suggest that KDM6A loss is a mechanism of Dara resistance in MM, and EZH2 inhibitors could improve MM responsiveness to Dara. The study also shows that KDM6A regulates CD48 expression, which is crucial for NK cell activation. CD48 loss reduces NK cell activity, leading to ADCC resistance. Overexpression of CD48 in KDM6A-KO cells restores ADCC sensitivity. EZH2 inhibitors increase CD38 and CD48 expression, enhancing Dara-mediated ADCC. The study highlights the role of KDM6A in epigenetic regulation of NK cell activity and provides a preclinical rationale for using EZH2 inhibitors in combination with Dara to overcome resistance in MM.