The tumor immune microenvironment has manifested a crucial correlation with tumor occurrence, development, recurrence, and metastasis. To explore the mechanisms intrinsic to osteosarcoma (OS) initiation and progression, this study synthesizes multiple single‐cell RNA sequencing data sets, constructing a comprehensive landscape of the OS microenvironment. Integrating single‐cell RNA sequencing with bulk RNA sequencing data has enabled the identification of a significant correlation between heightened expression of the fatty acid metabolism‐associated gene (C1QBP) and patient survival in OS. C1QBP not only amplifies the proliferation, migration, invasion, and anti‐apoptotic properties of OS but also instigates cisplatin resistance. Subsequent investigations suggest that C1QBP potentially promotes macrophage polarization from monocytes/macrophages toward M2 and M3 phenotypes. Consequently, C1QBP may emerge as a novel target for modulating OS progression and resistance therapy. [ABSTRACT FROM AUTHOR]