CRISPR-GEMM pooled mutagenic screening identifies KMT2D as a major modulator of immune checkpoint blockade

Immune checkpoint blockade (ICB) has shown remarkable clinical efficacy across multiple cancer types. However, only a fraction of patients respond to ICB. Here, we performed pooled mutagenic screening with CRISPR-mediated genetically engineered mouse models (CRISPR-GEMMs) in ICB settings, and identified KMT2D as a major modulator of ICB response across multiple cancer types. Kmt2d encodes a histone H3K4 methyltransferase and is among the most frequently mutated genes in cancer patients. Kmt2d loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. Additionally, Kmt2d-deficient cells exhibit increased protein turnover and IFNy-stimulated antigen presentation. In turn, Kmt2d-mutant tumors in both mouse and human are characterized by increased immune infiltration. These data demonstrate that KMT2D deficiency sensitizes tumors to ICB by augmenting tumor immunogenicity, highlighting the power of CRISPR-GEMMs for interrogating complex molecular landscapes in immunotherapeutic contexts that preserve the native tumor microenvironment.