EZH2 expression was negatively correlated with components of the antigen-processing machinery pathway in TCGA-HNSC and genetic ablation or pharmacological inhibition of EZH2 resulted in a significant increase of MHC class I expression on HNSCC cells, antigen-specific CD8-positive T cell proliferation, IFN-γ production, and tumor cell cytotoxicity. This evidence concerns the gene EZH2 and head and neck squamous cell carcinoma.