Glycoscience in Advancing PD-1/PD-L1-Axis-Targeted Tumor Immunotherapy

Immune checkpoint blockade therapy, represented by anti-PD-1/PD-L1 monoclonal antibodies, has significantly changed the immunotherapy landscape. However, the treatment is still limited by unsatisfactory response rates, immune-related adverse effects, and drug resistance. Current studies have established that glycosylation, a common post-translational modification, is crucial in promoting cancer progression and immune invasion. Targeting aberrant glycosylation in cancers presents precision medicine regimens for monitoring cancer progression and developing personalized medicine. Notably, the immune checkpoints PD-1 and PD-L1 are highly glycosylated, which affects PD-1/PD-L1 interaction and the binding of anti-PD-1/PD-L1 monoclonal antibodies. Recent achievements in glycoscience to enhance patient outcomes, referred to as glycotherapy, have underscored their high potency in advancing PD-1/PD-L1 blockade therapies, i.e., glycoengineered antibodies with improved binding toward PD-1/PD-L1, pharmaceutic inhibitors for core fucosylation and sialylation, and synergistic treatment with the antibody-sialidase conjugate. This review briefly introduces the PD-1/PD-L1 axis and glycosylation and highlights the fundamental and applied advances in glycoscience that improve PD-1/PD-L1 immunoblockade therapies.