Osteosarcoma (OS), the most common primary malignant bone tumor in children and adolescents, remains a major therapeutic challenge due to its high metastatic potential and limited response to conventional treatments, including immune checkpoint inhibitors (ICIs). Oncolytic viruses (OVs) have emerged as a promising strategy with dual antitumor functions: direct oncolysis and the induction of immunogenic cell death (ICD). By releasing damage-associated molecular patterns (DAMPs) and activating the cGAS–STING pathway, OVs can remodel the immunologically “cold” tumor microenvironment (TME) into an inflamed and immune-responsive phenotype, thereby enhancing CD8 + T-cell infiltration and improving antitumor immunity. Encouraging preclinical evidence has been reported: VSV-IFNβ-NIS achieved a long-term survival rate of approximately 35% in canine OS models, and synergistic combination regimens have demonstrated tumor inhibition rates exceeding 70%. Despite these advances, OV-based therapies still face critical translational challenges, including the immunosuppressive TME, intratumoral delivery barriers, and safety concerns. This review systematically summarizes the molecular mechanisms underlying OV-mediated antitumor immunity, evaluates current clinical evidence, and highlights future opportunities, such as combination immunotherapy, mesenchymal stem cell (MSC)-based delivery platforms, and AI-driven precision medicine approaches. Our goal is to provide a comprehensive theoretical framework to support the clinical translation and personalized application of OV therapy in osteosarcoma.
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