{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T09:30:32Z","timestamp":1786354232011,"version":"build-2736575974"},"reference-count":94,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Osteosarcoma (OS) prognosis remains stagnant due to the complex tumor microenvironment. This review deconstructs the \u201cmalignant synergy\u201d 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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1885433","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T08:45:56Z","timestamp":1786351556000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering the malignant synergy: metabolic reprogramming, epigenetic circuitry, and niche remodeling in osteosarcoma-macrophage crosstalk"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhi","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Chengdu Integrated TCM & Western Medicine Hospital","place":["Chengdu, 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