Radiation-Induced Tumor-Intrinsic LTβR N-Glycosylation Suppresses Pyroptosis Through TRIM28-Mediated PCBP2...

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.