New Horizons in Oncolytic Virotherapy for Osteosarcoma

Osteosarcoma is a highly aggressive malignant bone tumor characterized by an immunosuppressive microenvironment, with the five-year survival rate of metastatic patients remains dismally low. Oncolytic virotherapy has emerged as a promising strategy, utilizing both direct tumor lysis and immunity activation. This review systematically examines the latest advancements in oncolytic virus monotherapy Oncolytic monotherapy and combination therapy for osteosarcoma, drawing from preclinical models (e.g., mouse and canine studies) and clinical trials. In monotherapy, genetically engineered viruses such as VCN-01 (targeting integrin v3/5 via an RGD sequence and secreting hyaluronidase for stromal degradation) and Delta-24-ACT (expressing 4-1BBL to enhance T-cell activation) demonstrated significant tumor reduction and prolonged survival. VSV-IFN-NIS was well tolerated in canine models, improving long-term survival and upregulating T-cell immune responses. In combination therapy, oncolytic viruses enhanced the efficacy of chemotherapy (e.g., OBP-702 with doxorubicin), radiotherapy (e.g., E4orf6 virus), targeted drugs (e.g., VSV51 with PI3K inhibitor ZSTK474), and immune checkpoint inhibitors (e.g., CAV2-AU-M2 delivering anti-PD-1 antibodies). Despite these promising outcomes, challenges such as viral toxicity, limited delivery modes, and species-specific variability remain. Future strategies may include gene editing for improved tumor targeting, oncolytic virus-T-cell chimeras, and novel systemic delivery approaches to enhance therapeutic efficacy. Oncolytic virotherapy, in combination with multidisciplinary treatments, holds great potential to overcome current limitations amd improve survival outcomes for vosteosarcoma patients.