O -GlcNAcylation promotes tumor immune evasion by inhibiting PD-L1 lysosomal degradation.

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.