Radiation‐Induced Tumor‐Intrinsic LTβR N‐Glycosylation Suppresses Pyroptosis Through TRIM28‐Mediated PCBP2 SUMOylation to Promote Gastric Cancer Radioresistance

ABSTRACT Radiotherapy is important for advanced and metastatic gastric cancer (GC), but radioresistance limits its benefit. Pyroptosis has emerged as a potential strategy to overcome radioresistance, yet its regulatory mechanisms remain unclear. Using LC‐MS/MS‐based proteomic profiling of tumor tissues from patients with GC treated with neoadjuvant chemoradiotherapy, we identified tumor‐intrinsic lymphotoxin beta receptor (LTβR), previously considered mainly an immune cell membrane protein, as a candidate determinant of poor radiotherapy response. Functional studies in GC cell lines, xenografts, and patient‐derived organoids (PDOs) showed that LTβR depletion enhanced radiosensitivity, whereas LTβR overexpression promoted radioresistance. Integrated RNA‐seq, Ribo‐seq, and polysome profiling showed that LTβR loss reduced translational efficiency of SARM1 under irradiation. Mechanistically, irradiation increased LTβR stability in a glycosylation‐dependent manner and promoted nuclear translocation. In the nucleus, LTβR enhanced TRIM28‐mediated SUMOylation of PCBP2, promoting cytoplasmic redistribution of PCBP2 and increased translational efficiency of SARM1 . Consistently, LTβR suppressed irradiation‐induced pyroptosis through the NLRP3/caspase‐1/GSDMD pathway. We further identified EMD638683 as an LTβR‐binding compound through structure‐based virtual screening, and showed that cRGD‐modified liposomes improved its tumor‐targeted delivery and enhanced LTβR reduction, radiosensitization, and tumor suppression in PDO and xenograft models. Together, these findings highlight LTβR as a promising therapeutic target to improve radiotherapy efficacy in GC.