O‐GlcNAcylated TAP1 Impairs Antigen Presentation and Promotes Immune Evasion in Bladder Cancer

ABSTRACT Major histocompatibility complex class I (MHC‐I) proteins play a crucial role in immune surveillance by presenting newly synthesized antigens to CD8 ⁺ T cells on the cell surface. The downregulation of MHC‐I impairs antigen presentation and facilitates immune evasion in bladder cancer. O‐GlcNAcylation, an O‐linked N‐acetylglucosamine modification that is upregulated in various cancers, is increasingly recognized for its role in immune regulation. However, its specific role in antigen presentation remains unclear. In this study, we identified an inverse correlation between O‐GlcNAcylation levels and immune cell infiltration, specifically reducing CD8 ⁺ T cell numbers in bladder cancer. Reducing cellular O‐GlcNAcylation significantly enhanced antigen presentation efficiency. We demonstrated that O‐GlcNAcylation of antigen peptide transporter 1 (TAP1), a key transporter in the antigen presentation pathway, disrupts its interaction with MHC‐I, thereby promoting the autophagic‐lysosomal degradation of MHC‐I and impairing CD8 ⁺ T cell‐mediated cytotoxicity. Inhibiting O‐GlcNAcylation of TAP1 significantly augmented antitumor immune responses. Collectively, these findings reveal a novel mechanism by which O‐GlcNAcylation facilitates immune evasion in bladder cancer and suggest a potential therapeutic strategy for enhancing TAP/MHC‐I‐mediated antigen presentation.