Sarcoma is a kind of mesenchymal malignant tumor and often has poor chemotherapy response. There are many reasons for the insensitivity of sarcomas to chemotherapy, among which genetic changes are important. As a common type of gene alteration, gene fusion plays an important role in the pathogenesis and progression of tumors. In this study, we report a novel osteosarcoma-associated fusion gene, EWSR1-PSMC5, found in patients insensitive to chemotherapy. This gene is a novel fusion mode and has been found to play an important role in autophagy activation. The fusion gene may lead to the activation of autophagy through various signaling pathways, thus leading to the development of osteosarcoma resistance. We report this new fusion mode for the first time, and it should be noted that there is a less common report of EWSR1-related fusion gene in osteosarcoma.