Checkpoints (ITGB2, HAVCR2, and LGALS9), cytokine (ITGB1), growth factor (ITGB2, SDC2, PGF, and TGFB1), and other (CD63, COL1A1, COL1A2, and TIMP1) were the most active signaling pathways involved in the cell communication between osteosarcoma cells with a high mitochondria-related signature score and microenvironment cells, indicating the potential immune evasion and tumor progression in osteosarcoma cells with a high mitochondria-related signature score. This evidence concerns the gene SDC2 and osteosarcoma.