Abstract Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with recurrent loss-of-function alterations in polycomb-repressive complex 2 (PRC2), a histone-modifying complex involved in transcriptional silencing. To understand the role of PRC2 loss in pathogenesis and identify therapeutic targets, we conducted parallel global epigenomic and proteomic analysis of archival formalin-fixed, paraffin-embedded (FFPE) human MPNST with and without PRC2 loss (MPNSTLOSS vs. MPNSTRET). Loss of PRC2 resulted in increased histone posttranslational modifications (PTM) associated with active transcription, most notably H3K27Ac and H3K36me2, whereas repressive H3K27 di- and trimethylation (H3K27me2/3) marks were globally lost without a compensatory gain in other repressive PTMs. Instead, DNA methylation globally increased in MPNSTLOSS. Epigenomic changes were associated with upregulation of proteins in growth pathways and reduction in IFN signaling and antigen presentation, suggesting a role for epigenomic changes in tumor progression and immune evasion, respectively. These changes also resulted in therapeutic vulnerabilities. Knockdown of NSD2, the methyltransferase responsible for H3K36me2, restored MHC expression and induced interferon pathway expression in a manner similar to PRC2 restoration. MPNSTLOSS were also highly sensitive to DNA methyltransferase and histone deacetylase (HDAC) inhibitors. Overall, these data suggest that global loss of PRC2-mediated repression renders MPNST differentially dependent on DNA methylation to maintain transcriptional integrity and makes them susceptible to therapeutics that promote aberrant transcription initiation. Significance: Global profiling of histone PTMs and protein expression in archival human MPNST illustrates how PRC2 loss promotes oncogenesis but renders tumors vulnerable to pharmacologic modulation of transcription. See related commentary by Natarajan and Venneti, p. 3172