<p>Osteosarcoma (OS) is the most prevalent and aggressive primary malignant bone tumor, characterized by early metastasis and a poor prognosis, particularly in patients resistant to conventional multimodal therapies. As survival rates have plateaued, identifying novel therapeutic vulnerabilities is imperative. Ferroptosis, an iron-dependent form of regulated cell death driven by lethal lipid peroxidation, offers a distinct mechanism to overcome drug resistance in OS cells, which frequently exhibit metabolic dependency on iron. This review comprehensively elucidates the regulatory networks of ferroptosis in OS, with a specific focus on the System Xc⁻/Glutathione Peroxidase 4 (GPX4) antioxidant axis and lipid metabolism. Beyond direct cytotoxicity, we critically examine the synergistic interplay between ferroptosis and the tumor immune microenvironment (TME). Ferroptosis induction triggers immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs), which promotes dendritic cell maturation and enhances CD8⁺ T cell cytotoxicity. Furthermore, we discuss the mechanistic crosstalk by which ferroptosis remodels the immunosuppressive landscape, specifically affecting the polarization of tumor-associated macrophages (TAMs) and the stability of regulatory T cells (Tregs). Finally, the review addresses critical challenges for clinical translation, including tumor heterogeneity, safety concerns regarding off-target toxicity, and the urgent need for predictive biomarkers and advanced nanodelivery systems. This integrated perspective highlights ferroptosis-based combination immunotherapy as a promising frontier for personalized medicine in osteosarcoma. </p> Graphical abstract <p>Schematic diagram: Tumor microenvironment and the antioxidant defense mechanism of ferroptosis. System Xc⁻, Amino acid transport system; Glu, glutamate; Gly, glycine; GPX4, Glutathione Peroxidase 4; GSH, Glutathione; DC cell, Dendritic Cell; PLOOH, lipid peroxides.</p> <p></p>