Deciphering the malignant synergy: metabolic reprogramming, epigenetic circuitry, and niche remodeling in osteosarcoma-macrophage crosstalk.

Osteosarcoma (OS) prognosis remains stagnant due to the complex tumor microenvironment. This review deconstructs the "malignant synergy" between OS cells and tumor-associated macrophages (TAMs). Beyond the traditional M1/M2 dichotomy, we highlight the functional heterogeneity of TAMs, tracking their evolution from resident defenders to pro-metastatic accomplices. We elucidate three critical mechanisms driving this domestication: (1) Metabolic Reprogramming, where OS cells enforce immunosuppression via amino acid and lipid hijacking; (2) Epigenetic Circuitry, involving m6A modifications and ceRNA networks that create self-reinforcing malignant loops; and (3) Niche Remodeling, where exosomal fusion proteins remotely condition the lung for metastasis. By synthesizing these mechanisms, we identify key vulnerabilities in immune evasion and chemoresistance, providing a rationale for therapies targeting this critical interaction.