ATRXis one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role ofATRXin tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed thatAtrx-deleted tumors were more sensitive to radiation therapy and to oncolytic herpesvirus. In the absence ofAtrx, irradiated sarcomas had increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. Our work also showed thatAtrxdeletion resulted in downregulation of the CGAS/STING signaling pathway at multiple points in the pathway and was not driven by mutations or transcriptional downregulation of the CGAS/STING pathway components. We found that both human and mouse models ofAtrx-deleted sarcoma had a reduced adaptive immune response, markedly impaired CGAS/STING signaling, and increased sensitivity to TVEC, an oncolytic herpesvirus that is currently FDA approved for the treatment of aggressive melanomas. Translation of these results to patients withATRX-mutant cancers could enable genomically guided cancer therapy approaches to improve patient outcomes.