Bone niche-driven antitumor immune failure in osteosarcoma: Mechanisms and therapeutic implications (Review)

Osteosarcoma (OS) remains a clinically challenging primary malignant bone tumor that occurs predominantly in children, adolescents and young adults. Despite standard multimodal therapy, recurrent, metastatic and chemotherapy-refractory disease continues to have poor outcomes, and pulmonary recurrence remains a dominant cause of mortality. Tumor cell-intrinsic alterations, including genomic instability, clonal heterogeneity, stem-like plasticity and chemoresistance, explain important aspects of disease aggressiveness; however, they do not fully account for the limited responses to immune checkpoint blockade or engineered cellular therapies, nor for the high frequency of lung relapse after apparently adequate local control. The current review presents an evidence-graded bone niche-driven framework of layered antitumor immune failure in OS. In this model, the skeletal niche is not treated as a passive anatomical background but as a spatial and temporal organizer of immune-cell trafficking, myeloid remodeling, treatment-induced repair programs, systemic niche communication and pulmonary immune surveillance. Bone niche remodeling and myeloid-cell enrichment constitute the most mature mechanistic anchors, whereas pulmonary niche conditioning, efferocytosis, extracellular vesicle (EV)-mediated bone-lung signaling, and physical or metabolic stress adaptation are presented as emerging or hypothesis-generating modules. To prevent conceptual overextension, direct OS evidence is separated from contextual tumor-biology evidence and aligned with each claim, along with its current gap and a falsifiable validation route. Translationally, the framework supports a timed sequence of niche reprogramming, immune activation, and pulmonary niche maintenance, to be tested through perioperative window studies, paired primary-tumor and lung-metastasis cohorts, functional perturbation experiments, spatial immune profiling, circulating EV/chemokine monitoring and predefined pulmonary recurrence endpoints.