SKP2 and osteosarcoma: These mechanistic insights into osteosarcoma tumor biology and Skp2 function suggest novel targets for new, synergistic therapies, whereas the data and our comprehensive analysis may serve as a public resource for further big data-driven osteosarcoma research.<h4>Significance</h4>Our single-cell study of murine osteosarcoma models uncovers Skp2 function in metastasis, genomic instability, and immune activation and reveals additional target pathways to overcome resistance to Skp2 disruptions.