Extracellular vesicle-mediated immune escape in osteosarcoma: mechanisms, evidence gaps and translational priorities

Osteosarcoma remains the most common primary malignant bone tumor in children and young adults, characterized by an intricate tumor microenvironment (TME) and stagnant survival rates for metastatic disease. Extracellular vesicles (EVs) have emerged as pivotal mediators of intercellular communication within this ecosystem. This review synthesizes how osteosarcoma-derived EVs orchestrate immune evasion and drive premetastatic niche (PMN) formation. We focus on the best-characterized tumor-immune axes—specifically tumor-associated macrophages (TAMs), T lymphocytes, and myeloid-derived suppressor cells (MDSCs)—while cataloging unmapped territories (e.g., dendritic, NK, and B cells) as critical evidence gaps. We delineate the molecular mechanisms by which EV-encapsulated proteins and non-coding RNAs reprogram TAMs toward an immunosuppressive M2-like phenotype, attenuate T cell proliferation via EV-associated PD-L1/PD-1 interactions, and recruit PMN-MDSCs to establish a permissive lung microenvironment. Furthermore, we discuss the role of EVs in transferring multidrug resistance and promoting angiogenesis. While EV stability and their disease-associated molecular cargo position them as theoretical candidates for future liquid biopsy applications and therapeutic vehicles, critical gaps remain. Mechanistic plausibility is strong for limited tumor-immune circuits, yet human source attribution, standardized EV characterization, independent biomarker validation, and therapeutic translation remain major bottlenecks. Addressing these challenges is imperative for the clinical advancement of EV-based strategies in osteosarcoma.