In this study, we investigated the role of S1P in osteosarcoma-associated angiogenesis and the contribution of tumor acidosis to this process.<h4>Methods</h4>Matrigel®-based angiogenesis assays, HUVEC cultures, 3D osteosarcoma spheroids, and microfluidic systems were employed to evaluate endothelial sprouting and tubulogenesis. The gene discussed is MBTPS1; the disease is osteosarcoma.