Here, using both human MPNST tissues and engineered PRC2-loss murine models, we demonstrated that tumor-intrinsic PRC2 loss promoted immune evasion and an immune-desert TME through epigenetic reprogramming and consequent deficiency in antigen presentation, chemokine production, and IFN-γ signaling, as well as primary resistance to immune checkpoint blockade (ICB). This evidence concerns the gene IFNG and neoplasm.