肿瘤细胞治疗研究
英文原题：FUT2 enhances anti-tumor immunity in pancreatic cancer radiotherapy by driving FBXO2-mediated degradation of NR2F2.
胰腺导管腺癌（PDAC）的放疗（RT）耐药常由免疫抑制性肿瘤微环境（TIME）介导。
胰腺导管腺癌（PDAC）放疗（RT）耐药常由免疫抑制性肿瘤微环境（TIME）介导。通过体内CRISPR-Cas9代谢酶筛选，我们鉴定出岩藻糖基转移酶2（FUT2）是RT反应的有效非催化增强因子。机制上，FUT2支架E3泛素连接酶FBXO2，促进转录因子NR2F2的K362位点特异性泛素化及蛋白酶体降解。该降解抑制免疫抑制因子Lipocalin-2（LCN2）的表达，而LCN2驱动CD8⁺ T细胞耗竭并阻碍NK细胞浸润，从而形成放射抵抗性TIME。有趣的是，我们观察到RT可通过METTL14介导的m⁶A RNA甲基化降低FUT2转录本水平，而NR2F2被鉴定为转录上调METTL14，建立了一个维持FUT2抑制的前馈抑制环路。临床上，FUT2表达与RT治疗的PDAC患者中CD8⁺ T细胞浸润及生存期延长呈正相关。临床前，RT联合LCN2中和抗体可引发协同抗肿瘤免疫。这些结果揭示了FUT2通过FUT2-FBXO2-NR2F2-LCN2轴调控PDAC放射敏感性的作用，为克服RT耐药提供了一个有前景的治疗靶点。
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.
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