{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:10:00Z","timestamp":1787663400784,"version":"build-2736575974"},"reference-count":260,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Osteosarcoma (OS) is the most common primary bone cancer in adolescents and young adults. Despite tremendous preclinical and clinical efforts to advance therapy for OS, the standard of care, consisting of surgical resection and pre- and postoperative chemotherapy, has remained unchanged for over 40 years. Growing molecular understanding of OS highlights tumor heterogeneity as a major obstacle to therapeutic advances. In this narrative review, we comprehensively discuss current evidence of OS heterogeneity and strategies to overcome the barrier. Evidence shows that OS heterogeneity is multifactorial: it retains complex and dynamic somatic genomics, including genomic instability, alterations in tumor suppressors, and amplification\/overexpression of oncogenes such as MYC. The tumor is associated with various germline vulnerabilities. OS\u2019s tumor microenvironment has intense cellular and spatial diversity, which significantly shapes its heterogeneity. The effects of lineage plasticity, as well as epigenetic and metabolomic mechanisms, on OS heterogeneity are under study. To overcome this extreme heterogeneity, the therapeutic strategies for OS must be comprehensive and diversified. While surgical resection remains a mainstay of treatment, efforts to identify actionable biomarkers that guide risk stratification and therapy are ongoing. Diverse preclinical models offer insights into OS biology and novel therapeutics. To enhance combinational therapy for OS, various agents, including multi-targeted receptor tyrosine kinase inhibitors, immunotherapies, and epigenetic and metabolic modifiers, are being investigated. Distinctive efforts are continuing to establish maintenance therapy for OS. In summary, elucidating the complex drivers of OS heterogeneity, together with the development of multifaceted strategies to address them, is critical to accelerating therapeutic progress in OS.<\/jats:p>","DOI":"10.3390\/biom16060874","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:49:42Z","timestamp":1781743782000},"page":"874","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Understanding and Overcoming Osteosarcoma Heterogeneity"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4966-329X","authenticated-orcid":false,"given":"Sukjoo","family":"Cho","sequence":"first","affiliation":[{"name":"Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Atlanta, GA 30329, USA"},{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7359-7978","authenticated-orcid":false,"given":"Katherine","family":"Shelmidine","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Cancer Biology Program, Graduate Division of Biological and Biomedical Sciences, Emory University Laney Graduate School, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason T.","family":"Yustein","sequence":"additional","affiliation":[{"name":"Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Atlanta, GA 30329, USA"},{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1002\/cncr.34163","article-title":"Osteosarcoma: A Surveillance, Epidemiology, and End Results program-based analysis from 1975 to 2017","volume":"128","author":"Cole","year":"2022","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1056\/NEJM198606193142502","article-title":"The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity","volume":"314","author":"Link","year":"1986","journal-title":"N. 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