Magnesium phosphate cement modulates osteosarcoma stemness and osteogenesis via IGFBP5 activation for localized tumor therapy

• Magnesium phosphate cements (MPCs) inhibit the growth, spread, and stem cell-like properties of osteosarcoma cells in a dose-dependent manner. • MPCs promote osteogenic differentiation through matrix mineralization and activation of bone-related genes. • Insulin-like growth factor binding protein 5 (IGFBP5) is a key mediator that links MPCs treatment to both tumor suppression and osteogenic differentiation. • Silencing IGFBP5 reverses the therapeutic effects of MPCs on tumor cells, while in animal models MPCs reduce tumor growth and lung metastasis Osteosarcoma remains a clinical challenge due to aggressive bone destruction and cancer stem cell (CSC)-driven recurrence. While magnesium phosphate cement (MPC) is widely recognized for its osteoregenerative properties, its therapeutic potential in bone malignancies is largely unexplored. Here, we systematically evaluated MPCs with varying Mg/P ratios (MPC-1 ∼ 5) for their antitumor and pro-differentiation effects against osteosarcoma. MPC1 ∼ 3 demonstrated dose-dependent suppression of tumor growth, migration, and aggression, while MPC-5 elicited significant cytotoxicity. Notably, MPC-1 ∼ 3 suppressed CSC markers and promoted osteogenic differentiation, evidenced by matrix mineralization and upregulation of osteogenic transcription factors. In orthotopic and metastatic mouse models, MPC treatment significantly reduced tumor burden and pulmonary metastasis, alongside elevated expression of osteogenic markers (OPN, Runx2, Collagen-I). Mechanistically, MPCs upregulated insulin-like growth factor binding protein 5 (IGFBP5), that mediated stemness suppression and differentiation induction; silencing IGFBP5 reversed these effects. These findings identify MPC as a bifunctional biomaterial with both antitumor and osteoinductive properties, offering a promising strategy for osteosarcoma therapy via stemness-targeted differentiation.