The study investigates the epigenetic regulation of CD38/CD48 by KDM6A in multiple myeloma (MM) and its impact on the sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Through two genome-wide CRISPR screens, KDM6A is identified as a key regulator of CD38 and CD48 expression. Loss of KDM6A increases H3K27me3 levels on the promoters of CD38 and CD48, leading to their downregulation. This results in reduced ADCC activity. Reintroducing CD38 does not fully restore ADCC sensitivity, suggesting additional KDM6A targets are involved. Inhibition of H3K27me3 with an EZH2 inhibitor restores CD38 and CD48 expression and enhances sensitivity to Daratumumab. These findings suggest that KDM6A loss is a mechanism of Daratumumab resistance and that EZH2 inhibitors could be therapeutic for improving MM responsiveness to Daratumumab.The study investigates the epigenetic regulation of CD38/CD48 by KDM6A in multiple myeloma (MM) and its impact on the sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Through two genome-wide CRISPR screens, KDM6A is identified as a key regulator of CD38 and CD48 expression. Loss of KDM6A increases H3K27me3 levels on the promoters of CD38 and CD48, leading to their downregulation. This results in reduced ADCC activity. Reintroducing CD38 does not fully restore ADCC sensitivity, suggesting additional KDM6A targets are involved. Inhibition of H3K27me3 with an EZH2 inhibitor restores CD38 and CD48 expression and enhances sensitivity to Daratumumab. These findings suggest that KDM6A loss is a mechanism of Daratumumab resistance and that EZH2 inhibitors could be therapeutic for improving MM responsiveness to Daratumumab.