Disrupting Lipid Raft Microdomains to Block Polyploid Giant Cancer Cell Budding and Enhance Radiotherapy Response

Abstract Radiotherapy failure often arises from tumor repopulation by treatment‐resistant cancer cells. Following irradiation, cancer cells can undergo endoreplication to form polyploid giant cancer cells (PGCCs)—radiation‐persistent cells capable of generating progeny through a virus‐like 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‐induced SNCG–FLOT2–CHMP4B 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–enriched membrane microdomains, followed by CHMP4B‐dependent abscission to release daughter cells. Disrupting these lipid raft structures—via statins or anti‐PCSK9 antibodies—impairs budding, suppresses PGCC‐derived 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‐lowering agents may thus serve as innovative radiosensitizers to improve radiotherapy outcomes.