Abstract Epigenetic modifications including altered DNA methylation and histone posttranslational modifications (PTM) are central to the biology of several cancers. These modifications can regulate DNA accessibility and consequently, gene expression. In this issue, Wojcik and colleagues explore epigenetic drivers of malignant peripheral nerve sheath tumors (MPNST) harboring loss-of-function polycomb-repressive complex 2 mutations. They demonstrate alterations in specific histone PTMs and a global increase in DNA methylation. Notably, epigenetic alterations related with aberrant upregulation of proteins involved in immune evasion, which informed identification of potential therapeutic vulnerabilities. This study helps understand the complex biology of MPNSTs and may enable future therapeutic development. See related article by Wojcik et al., p. 3205