The hexosamine biosynthetic pathway drives tumor immune evasion via translational control of PD-L1 at the elongation level

作者：Bo Liu, Yingying Wu, An-Yi Xiang, Yiyi Yu, Shushu Song, Ying Zhang, Jianxin Gu, Haojie Lu, Ping Xu, Fenglin Liu, Yuanyuan Ruan · 发表于：Cell Reports · 年份：2025 · DOI：10.1016/j.celrep.2025.116249 · 被引用次数：6 · 研究领域：Glycosylation and Glycoproteins Research、Cancer, Hypoxia, and Metabolism、Peptidase Inhibition and Analysis

T lymphocyte infiltration in a colorectal cancer model. GFAT1 induced the expression of the immune checkpoint PD-L1 at the translational level by bypassing signal peptide-mediated translation elongation arrest. Proteomic and glycoproteomic screening indicated that GFAT1 facilitated the N-linked glycosylation and protein expression of integrin α2/α3 subunits, leading to FAK activation and elongation factor eEF1A2 upregulation. Pharmacological inhibition of HBP noticeably enhanced the efficacy of immune checkpoint blockade in vivo. Together, these findings unravel how immune checkpoint proteins are manipulated by metabolic dysregulation, which can be exploited as metabolic vulnerability for improving immunotherapies.