Gene-based immunotherapy in osteosarcoma: from oncolytic vectors to engineered immune cells

Osteosarcoma remains difficult to cure once it metastasizes, recurs, or becomes resistant to chemotherapy. Surgery combined with multi-drug chemotherapy improves outcomes in localized disease, but outcomes for high-risk patients have plateaued, prompting renewed interest in immunotherapy. However, immune checkpoint blockade has limited efficacy in unselected osteosarcoma patients: in SARC028, one objective response was observed among 22 patients with osteosarcoma treated with pembrolizumab. This limited response is consistent with antigen heterogeneity, enrichment of immunosuppressive myeloid populations, insufficient cytotoxic lymphocyte infiltration, matrix-associated immune exclusion, and metastatic immune adaptation. Gene-based immunotherapy offers a complementary strategy. When endogenous immune priming is inadequate, these platforms may initiate, reshape, or amplify antitumor immunity by promoting oncolytic antigen release, local cytokine or chemokine expression, engineered immune-cell recognition, or non-viral delivery of immunomodulatory payloads. This article discusses oncolytic vectors, cytokine-armed vectors, CAR-T and CAR-NK cells, TCR- or neoantigen-directed strategies, and non-viral gene delivery systems as potential approaches for reshaping osteosarcoma immunity. It also examines combination strategies and translational challenges in pediatric and adolescent patients. Beyond summarizing platform-level evidence, we distinguish findings generated directly in osteosarcoma from evidence extrapolated from other tumor types, identify the principal unresolved knowledge gaps for each platform, and summarize the current osteosarcoma-specific clinical trial landscape to clarify the translational maturity of these strategies.