Using a quantitative surface proteomics approach combined with epigenomic/transcriptomic analysis, we uncovered an immunomodulatory effect of DNMTis to facilitate tumor cytolysis by MHC-unrestricted γδ T cell-based therapy via upregulation of adhesion molecules and reorganization of the immunosynaptic cytoskeleton networks to strengthen the encounter between cancer and γδ T cells. Here, HLA-C is linked to cancer.