Phytochemical-drug combinations in osteosarcoma: Mechanistic vulnerabilities, evidence quality and translational challenges.

Osteosarcoma remains a major therapeutic challenge because of metastatic progression, recurrence and intrinsic or acquired resistance to conventional chemotherapy. Phytochemicals have emerged as potential complementary agents because of their ability to modulate multiple biological processes associated with osteosarcoma progression and treatment resistance. This review evaluates the mechanistic basis, pharmacological evidence and translational potential of phytochemical-drug combinations in osteosarcoma, with particular emphasis on redox regulation, DNA damage and repair, survival signalling, regulated cell death and metastatic progression. The available evidence indicates that phytochemicals can suppress osteosarcoma growth through apoptosis and cell-cycle arrest, while also modulating oxidative stress, ferroptosis, autophagy, epithelial-mesenchymal transition and oncogenic signalling pathways. Selected combinations with cisplatin or doxorubicin demonstrate enhanced chemosensitivity through modulation of pathways including PI3K/Akt, Wnt/β-catenin, STAT3, NF-κB and Nrf2/SLC7A11/GPX4, with ferroptosis emerging as a potential strategy for exploiting redox vulnerabilities in resistant disease. However, increased cytotoxicity or reduced chemotherapy IC50 values should not be interpreted as pharmacological synergy without quantitative combination analysis. Most evidence remains derived from conventional two-dimensional cell models, while poor bioavailability, uncertain tumour exposure, pharmacokinetic interactions and limited toxicity data remain important translational barriers. A Mechanism-Interaction-Translation framework is proposed to prioritize promising combinations based on biological vulnerability, quantitatively validated drug interaction and confirmation of efficacy and tolerability in increasingly relevant models. Overall, phytochemical-drug combinations represent a promising preclinical strategy for improving therapeutic responses in osteosarcoma, but further mechanistically validated, pharmacokinetically feasible and clinically relevant studies are required before their therapeutic efficacy can be established.