The bone vicious cycle: How the microenvironment drives osteosarcoma progression

Osteosarcoma progression cannot be fully explained by tumor-intrinsic genetic alterations alone; it is shaped by continuous interactions with the bone microenvironment. Emerging evidence indicates that osteosarcoma cells actively sense, appropriate, and remodel bone-specific structural, metabolic, and immune programs, establishing a self-reinforcing niche that supports tumor growth, immune evasion, and therapeutic resistance. We integrate multi-level mechanistic insights into a unified conceptual framework-the bone-specific vicious cycle-which conceptualizes osteosarcoma evolution as a staged process encompassing niche initiation, amplification, and stabilization. Mechanical signals derived from the rigid bone matrix, calcium-driven proliferative circuits, osteoclast-mediated bone destruction, metabolic immunosuppression, and extracellular matrix remodeling are proposed to collectively drive the remodeling of the physiological bone niche toward an immune-excluded, tumor-supportive state. This stabilized cycle not only sustains malignant progression but also underlies both primary and acquired resistance to conventional and immunologically based therapies. By integrating cellular, metabolic, and immunological dimensions, this framework highlights actionable nodes for intervention and indicates that disrupting niche-level feedback loops is a prerequisite for restoring therapeutic sensitivity in osteosarcoma. Reframing osteosarcoma as an ecological disease provides a rationale for combination strategies targeting both tumor cells and the bone microenvironment.