Post-translational regulations of PD-L1 and PD-1: Mechanisms and opportunities for combined immunotherapy

Antibodies targeting programmed cell death protein 1 (PD-1) or its ligand programmed death-ligand 1 (PD-L1) are profoundly changing the methods to treat cancers with long-term clinical benefits. Unlike conventional methods that directly target tumor cells, PD-1/PD-L1 blockade exerts anti-tumor effects largely through reactivating or normalizing cytotoxic T lymphocyte in the tumor microenvironment to combat cancer cells. However, only a small fraction of cancer patients responds well to PD-1/PD-L1 blockade and clinical outcomes have reached a bottleneck without substantial advances. Therefore, better understanding the molecular mechanisms underlying how PD-1/PD-L1 expression is regulated will provide new insights to improve the efficacy of current anti-PD-1/PD-L1 therapy. Here, we provide an update of current progress of PD-L1 and PD-1 post-translational regulations and highlight the mechanism-based combination therapy strategies for a better treatment of human cancer.