程序死亡配体1（PD-L1）及其受体程序性细胞死亡1（PD-1）介导T细胞依赖性免疫攻击肿瘤。表面PD-L1细胞的丰度是靶向PD-L1的免疫检查点阻断疗法的疗效的关键决定因素。然而，表面PD-L1的调节仍然不清楚。我们在这里展示，PD-L1的溶酶体降解由O-连接N-乙酰氨基葡萄糖（O-GlcNAc）在细胞内运输途径期间调节。O-GlcNAc修饰肝细胞生长因子调节的酪氨酸激酶底物（HGS），是内体分拣机制的关键组分，随后抑制其与细胞内PD-L1的相互作用，导致PD-L1的溶酶体降解受损。O-GlcNAc的抑制在体内和具有免疫能力的小鼠中激活T细胞介导的抗肿瘤免疫，该作用取决于HGS的糖基化。O-GlcNAc抑制与PD-L1抗体的联合更能协同促进抗肿瘤免疫反应。我们还设计了一个HGS糖基化的竞争性肽抑制剂，可降低PD-L1表达并增强T细胞介导的免疫攻击肿瘤细胞的能力。总体而言，我们的研究揭示了O-GlcNAc与肿瘤免疫逃避之间的联系，并提出了改善PD-L1介导的免疫检查点阻断疗法的策略。

Programmed-death ligand 1 (PD-L1) and its receptor programmed cell death 1 (PD-1) mediate T cell-dependent immunity against tumors. The abundance of cell surface PD-L1 is a key determinant of the efficacy of immune checkpoint blockade therapy targeting PD-L1. However, the regulation of cell surface PD-L1 is still poorly understood. Here, we show that lysosomal degradation of PD-L1 is regulated by O-linked N-acetylglucosamine (O-GlcNAc) during the intracellular trafficking pathway. O-GlcNAc modifies the hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), a key component of the endosomal sorting machinery, and subsequently inhibits its interaction with intracellular PD-L1, leading to impaired lysosomal degradation of PD-L1. O-GlcNAc inhibition activates T cell-mediated antitumor immunity in vitro and in immune-competent mice in a manner dependent on HGS glycosylation. Combination of O-GlcNAc inhibition with PD-L1 antibody synergistically promotes antitumor immune response. We also designed a competitive peptide inhibitor of HGS glycosylation that decreases PD-L1 expression and enhances T cell-mediated immunity against tumor cells. Collectively, our study reveals a link between O-GlcNAc and tumor immune evasion, and suggests strategies for improving PD-L1-mediated immune checkpoint blockade therapy.