The clinical outcomes of osteosarcoma are relatively dismal. As immunotherapy has revolutionized treatment for solid tumors, exploring novel immunotherapy‐related therapeutic targets for osteosarcoma is important. In this study, we aimed to establish the connection between RNA modification and immunotherapy in osteosarcoma to identify novel therapeutic targets. An RNA modification‐related signature was first developed using weight gene correlation network analysis and a machine‐learning algorithm, random forest. The signature's prognostic value, drug prediction, and immune characteristics were analyzed. EIF4G2 from the signature was next identified as a critical immunotherapy determinant. EIF4G2 could also promote tumor proliferation, migration, and M2 macrophage migration by single‐cell sequencing analysis and in vitro validation. Our signature and EIF4G2 are expected to provide valuable insights into the clinical management of osteosarcoma.