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

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.