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Radioresistance is a main reason for treatment failure in patients with small cell lung cancer (SCLC). Consequently, it is important to determine the key mechanism and explore effective strategies to prevent SCLC radioresistance. We use an unbiased CRISPR screen to identify GSDME, a member of the Gasdermin (GSDM) family, as a critical driver of radiosensitivity in SCLC. Furthermore, we identify mTORC2 facilitates SCLC radioresistance by inhibiting GSDME-N-mediated pyroptosis. Mechanistically, mTORC2 phosphorylates GSDME-N at serine 114 (S114), promoting the recruitment of the CUL4B-RBBP4 E3 ubiquitin ligase complex. This complex mediates K48-linked ubiquitination of GSDME-N at lysine 41 (K41), leading to its proteasomal degradation. Clinically, elevated mTORC2 is linked to an unfavorable prognosis in SCLC patients. The study reveals mTORC2 phosphorylates GSDME-N and promotes its Cullin4B-mediated proteasomal degradation to suppress pyroptosis and drive radioresistance in SCLC.