Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity.

摘要: New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed. When exploring PD-L1-targeted effects mechanistically diverse metabolism-targeting drugs, exposure dietary polyphenol resveratrol (RSV) revealed its differential capacity generate a distinct PD-L1 electrophoretic migration pattern. Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as direct inhibitor glyco-PD-L1-processing enzymes (α-glucosidase/α-mannosidase) modulate N-linked glycan decoration PD-L1, thereby promoting endoplasmic reticulum retention mannose-rich, abnormally glycosylated form PD-L1. was also predicted interact with inner surface involved in interaction PD-1, almost perfectly occupying target space small compound BMS-202 binds induces dimerization The ability directly interferes stability trafficking, ultimately impeding targeting cancer cell plasma membrane. Impedance-based real-time analysis (xCELLigence) showed cytotoxic T-lymphocyte notably exacerbated when cells were previously exposed RSV. This unforeseen immunomodulating mechanism might illuminate new approaches restore T-cell function by PD-1/PD-L1 immunologic checkpoint natural polyphenols.