FUT2 enhances anti-tumor immunity in pancreatic cancer radiotherapy by driving FBXO2-mediated degradation of NR2F2

Abstract Pancreatic ductal adenocarcinoma (PDAC) radiotherapy (RT) resistance is frequently mediated by an immunosuppressive tumor microenvironment (TIME). Utilizing an in vivo CRISPR-Cas9 metabolic enzyme screen, we identified fucosyltransferase 2 (FUT2) as a potent non-catalytic enhancer of RT response. Mechanistically, FUT2 scaffolds the E3 ubiquitin ligase FBXO2, facilitating K362 site-specific ubiquitination and proteasomal degradation of the transcription factor NR2F2. This degradation suppresses expression of the immunosuppressive factor Lipocalin-2 (LCN2), which drives CD8⁺ T cell exhaustion and impedes NK cell infiltration, fostering a radioresistant TIME. Interestingly, we observed that RT could reduce FUT2 transcript levels via an METTL14-mediated m⁶A RNA methylation, while NR2F2 was identified to transcriptionally upregulate METTL14, establishing a feedforward inhibitory loop that sustains FUT2 suppression. Clinically, FUT2 expression positively correlates with CD8⁺ T cell infiltration and prolonged survival in RT-treated PDAC patients. Preclinically, combining RT with LCN2-neutralizing antibodies elicited synergistic anti-tumor immunity. These results unveil FUT2 as a regulator of PDAC radiosensitivity via the FUT2-FBXO2-NR2F2-LCN2 axis, offering a promising therapeutic target to overcome RT resistance.