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Following irradiation, cancer cells can undergo endoreplication to form polyploid giant cancer cells (PGCCs)\u2014radiation\u2010persistent cells capable of generating progeny through a virus\u2010like asymmetric budding process. While such membrane budding is evolutionarily conserved across archaea, viruses, and eukaryotic cells, its molecular mechanism in cancer remains poorly defined. Here, a radiation\u2010induced SNCG\u2013FLOT2\u2013CHMP4B signaling axis is identified as a key regulator of PGCC budding. Mechanistically, ASAH1 and SMPD2 maintain sphingolipid metabolic balance, while FLOT2 drives germination at lipid raft\u2013enriched membrane microdomains, followed by CHMP4B\u2010dependent abscission to release daughter cells. Disrupting these lipid raft structures\u2014via statins or anti\u2010PCSK9 antibodies\u2014impairs budding, suppresses PGCC\u2010derived tumor repopulation, and enhances radiosensitivity in vitro and in vivo. This findings uncover a conserved membrane remodeling program underlying PGCC budding and establish lipid raft disruption as a promising therapeutic approach to prevent tumor recurrence after radiotherapy. Clinically available lipid\u2010lowering agents may thus serve as innovative radiosensitizers to improve radiotherapy outcomes.<\/jats:p>","DOI":"10.1002\/advs.202519698","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T04:00:02Z","timestamp":1764734402000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Disrupting Lipid Raft Microdomains to Block Polyploid Giant Cancer Cell Budding and Enhance Radiotherapy Response"],"prefix":"10.1002","volume":"13","author":[{"given":"Zheng","family":"Deng","sequence":"first","affiliation":[{"name":"Cancer Center Shanghai General Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 201620 China"},{"name":"Shanghai Key Laboratory for Pancreatic Diseases Shanghai General Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 201620 China"},{"name":"Department of Urology Shanghai General Hospital Shanghai Jiao Tong 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