Starting from the bioinformatic analysis of publicly available CRISPR/Cas9 datasets for screening tumor-cell-intrinsic regulators of tumor immunity, we identified and characterized a previously unappreciated role of tumor-cell enhancer regulation by MLL3 and MLL4 in the control of T-cell-mediated killing and tumor immune response in multiple syngeneic murine cancer models. This evidence concerns the gene KMT2D and cancer.