Role of tumor-derived exosomes and immune cells in osteosarcoma progression and targeted therapy.

Osteosarcoma, the most common primary malignant bone tumor, poses significant clinical challenges due to its aggressive nature, high metastatic potential, and resistance to conventional therapies. Despite improvements in surgical and chemotherapeutic approaches, survival rates for relapsed or metastatic disease remain poor. Recent advances in understanding the tumor immune microenvironment (TIME) and exosome biology have uncovered critical mechanisms driving osteosarcoma progression, immune evasion, and therapeutic resistance. Tumor-associated macrophages (TAMs), particularly the M2 phenotype, dominate the osteosarcoma immune landscape and contribute to immunosuppression through cytokine secretion and modulation of T cell function. Exosomes, as intercellular messengers, further exacerbate tumor progression by transporting oncogenic proteins, immunosuppressive factors (TGF-β), miRNAs, and drug-resistance molecules. These vesicles also influence critical signaling cascades including Wnt/β-catenin and TGF-β pathways, shaping both local and systemic tumor responses. This review delineates the roles of immune cells and tumor-derived exosomes in osteosarcoma biology and evaluates emerging immunotherapeutic strategies, including immune checkpoint inhibitors, CAR-T cells, tumor vaccines, cytokine-targeted agents, and combination therapies. We highlight ongoing clinical trials, numerical efficacy metrics, and the translational promise of exosome-based diagnostics and therapeutics. Ultimately, integrated approaches targeting both the TIME and exosome-mediated mechanisms may yield more effective and durable treatments for osteosarcoma patients.