Advances in T cell-based immunotherapy for osteosarcoma.

Osteosarcoma, the most prevalent primary malignant bone tumor in children and adolescents, remains a formidable clinical challenge due to its high metastatic potential and limited therapeutic progress over the past three decades. While surgery combined with multi-agent chemotherapy has improved outcomes for patients with localized disease, prognosis for those with recurrent or metastatic osteosarcoma remains poor. Although immunotherapy has revolutionized cancer care across multiple malignancies, its efficacy in osteosarcoma has been modest, largely owing to an immunosuppressive tumor microenvironment, functional T cell exhaustion, and pronounced antigenic heterogeneity. Recent advances in T cell-based strategies, including MHC-independent γδ T cells, immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4, and chimeric antigen receptor (CAR) T cells directed against antigens such as HER2, GD2, and B7-H3, have demonstrated encouraging preclinical activity but limited clinical translation. Emerging evidence suggests that impaired antigen presentation, suppressive immune cell populations, and inadequate T cell trafficking collectively restrict therapeutic efficacy. This review summarizes recent mechanistic and translational advances in T cell-directed immunotherapy for osteosarcoma and proposes future directions to improve clinical outcomes.