Targeting the osteosarcoma immune microenvironment for improved immunotherapy and translational applications

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Despite advances in surgery and chemotherapy, outcomes remain poor in metastatic cases, with five-year survival rates below 30%. This stagnation highlights the urgent need for novel therapeutic strategies. Growing evidence indicates that the tumor immune microenvironment (TIME) plays a central role in OS progression, metastasis, and resistance to treatment. Immunosuppressive cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), dominate the TIME, while cytotoxic T cells often exhibit exhaustion. Stromal barriers, hypoxia, and metabolic constraints further impair immune activity. Recent single-cell and spatial transcriptomic studies reveal that immune and stromal architectures strongly correlate with prognosis and therapeutic response. These features contribute to the limited efficacy of current immunotherapies, including immune checkpoint inhibitors (ICIs) and CAR-T cells. In this review, we summarize the cellular, molecular, and spatial components of the OS TIME, critically evaluate current immunotherapeutic strategies, and highlight emerging translational approaches aimed at overcoming immune resistance and improving clinical outcomes.