{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T19:20:41Z","timestamp":1788895241124,"version":"build-2803163510"},"reference-count":121,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"U.S. Department of Defense","award":["PR201467"],"award-info":[{"award-number":["PR201467"]}]},{"name":"U.S. Department of Defense","award":["RA210159"],"award-info":[{"award-number":["RA210159"]}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"crossref","award":["AR084491"],"award-info":[{"award-number":["AR084491"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Osteosarcoma (OS), the most common primary malignant bone tumor in children and young adults, is characterized by aggressive behavior, frequent metastasis, and resistance to chemotherapy, resulting in poor clinical outcomes. Increasing evidence indicates that OS progression is not solely driven by tumor-intrinsic factors but is strongly influenced by dynamic interactions within the tumor microenvironment (TME). This literature review synthesizes current research on the roles of endothelial cells, fibroblasts, mesenchymal stromal cells, immune populations, and osteoclasts in OS pathogenesis, with emphasis on cell\u2013cell interactions mediated by direct contact, soluble factors, and extracellular vesicles. The studies demonstrate that these interactions promote tumor proliferation, immune evasion, extracellular matrix remodeling, metastatic dissemination, and therapeutic resistance. Adaptive responses of both tumor and stromal cells to environmental stressors contribute to chemoresistance and disease progression. Collectively, our findings highlight the multifactorial nature of OS driven by complex cellular crosstalk within the TME. Understanding these mechanisms highlights the limitations of conventional chemotherapy and encourages the development of combined therapeutic approaches, including targeted therapies, immunomodulation, and microenvironmental interventions. Continued investigation into tumor\u2013microenvironment interactions may facilitate the identification of actionable targets and improve personalized treatment approaches for OS.<\/jats:p>","DOI":"10.3390\/cells15060570","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:07:06Z","timestamp":1774271226000},"page":"570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cell\u2013Cell Interactome-Based Pathogenesis and Therapies for Osteosarcoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7032-2361","authenticated-orcid":false,"given":"Sriya","family":"Neelam","sequence":"first","affiliation":[{"name":"Department of Basic & Translational Sciences, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3465-0573","authenticated-orcid":false,"given":"Abdulaziz","family":"Hakeem","sequence":"additional","affiliation":[{"name":"Department of Basic and Translation Science, School of Dentistry, Umm Al Qura University, Mecca 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0875-6933","authenticated-orcid":false,"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Basic & Translational Sciences, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7126-6901","authenticated-orcid":false,"given":"Shuying","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Basic & Translational Sciences, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA 19104, USA"},{"name":"The Penn Center for Musculoskeletal Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Center for Innovation & Precision Dentistry, Penn Dental Medicine and School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Corre, I., Verrecchia, F., Crenn, V., Redini, F., and Trichet, V. 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