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High\u2010frequency amplification of the 17p11.2 chromosomal region in osteosarcoma represents a key molecular event driving malignant progression. This study focuses on the key gene COPS3 in this region, delving into its molecular mechanisms regulating cancer stemness. The findings show that elevated COPS3 expression strongly correlates with stemness features. Mechanistically, COPS3 binds directly to transcription factor SOX2, inhibiting its ubiquitin\u2010mediated degradation, enhancing its stability and transcriptional activity, and establishing a positive feedback loop that reinforces the stemness phenotype. Furthermore, the extracellular matrix receptor ITGB2 emerges as an upstream regulator promoting COPS3 nuclear translocation. Significantly, this study provides the first evidence that SOX2 undergoes liquid\u2010liquid phase separation (LLPS) in osteosarcoma, a critical mechanism for maintaining cancer stemness. Based on these findings, we identified Z\u20105891, a highly selective COPS3 inhibitor that suppresses tumor growth and reduces cancer stemness in vitro and in vivo. This study delineates a complete stemness regulatory pathway from microenvironmental signals to nuclear LLPS, thereby providing a novel theoretical framework and a candidate drug for targeting CSCs to overcome drug resistance and metastasis in osteosarcoma.<\/jats:p>","DOI":"10.1002\/advs.202520913","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T18:52:39Z","timestamp":1773427959000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The ITGB2\u2010COPS3\u2010SOX2 Axis and SOX2 Liquid\u2010Liquid Phase Separation: Dual Mechanisms Governing Osteosarcoma Stemness"],"prefix":"10.1002","volume":"13","author":[{"given":"Lei","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Orthopedics Peking University First Hospital Peking University  Beijing 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