Malignant peripheral nerve sheath tumors (MPNSTs), the most common and lethal malignant tumors in patients with Neurofibromatosis Type 1 (NF1), is characterized by recurrent biallelic inactivation of the NF1, CDKN2A and PRC2 components (EED or SUZ12). PRC2 loss in MPNST results in global loss of H3K27me2/3 and aberrant transcriptional activation of developmentally silenced master regulators, leading to enhanced cellular plasticity. PRC2 loss through epigenomic reprogramming also leads to aberrant activation of multiple signaling pathways (e.g. WNT signaling), an immune desert tumor microenvironment (TME), and primary resistance to immune checkpoint blockade (ICB). We hypothesize that PRC2 loss-mediated epigenomic reprograming underlines the molecular mechanisms of aberrant tumor heterogeneity and plastic behaviors in NF1-associated MPNST and represents a fundamental barrier for effective novel therapeutics. We further hypothesize that novel strategies aimed to reprogram the tumor cell epigenome and induces antigen presentation and innate antiviral immune responses may overcome the PRC2 loss tumor cell-specific cold TME, elicit anti-tumor immunity, and facilitate the development of novel immunotherapy combination. We proposed two specific aims for focused investigations: 1) Characterize the transcriptional plasticity and tumor heterogeneity and tumor evolution of NF1-associated MPNST under the selective pressure of TME in genetically defined in vitro and in vivo MPNST models. 2) Evaluate the impact of epigenomic reprograming of cancer cells by DNMT1 and bromodomain CBP/P300 inhibitors to elicit antigen presentation and innate immune responses, and to capitalize on cytotoxic T lymphocyte-mediated cancer cell immunotherapy in MPNST.