The negative effects on the expression of AGO2 and DNA methyltransferases by MLL4 loss promote double-stranded RNA (dsRNA) stress and derepress Gsdmd and inflammatory caspases to trigger interferon response and pyroptosis, which account for the increased anti-tumor immunity and immunotherapeutic efficacy induced by tumor cell-intrinsic MLL4 ablation. The gene discussed is KMT2D; the disease is neoplasm.