Soft tissue sarcomas are a diverse group of cancers that include undifferentiated pleomorphic sarcomas, which have a complex genome, and myxoid liposarcomas, which have a simple genome with a pathognomonic FUS-CHOP translocation, that is characterized by exquisite radiosensitivity. Using a biochemical approach, we discovered a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance and regulates radiation sensitivity. We identified novel protein interactions between FUS-CHOP and chromatin remodeling complexes that regulate sarcoma cell proliferation. Following ionizing radiation, DNA damage response kinases phosphorylate the prion-like domain of FUS-CHOP to impede these protein-protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupts oncogenic targeting of chromatin remodelers required for FUS-CHOP-driven sarcomagenesis. We have also generated a novel genetically engineered and carcinogen-induced mouse model of undifferentiated pleomorphic sarcoma. We find that when cell lines from this mouse model are transplanted into syngeneic mice that the combination of radiation therapy and anti-PD-1 cures all of the animals. However, the same combination treatment fails to cure the same tumor model in the absence of transplantation. Transplanted tumors have a tumor microenvironment that is enriched in T cells while autochthonous sarcomas have an immune landscape with fewer T cells that mimics most human sarcomas. These findings have important implications for ongoing sarcoma clinical trials testing radiation and immune checkpoint inhibition and mouse pre-clinical studies of immunotherapy.