Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway

Abstract

Targeting the programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway has evolved into one of the most promising strategies for tumor immunotherapy. Thus far, multiple monoclonal antibody drugs have been approved for treating a variety of tumors, while the development of small-molecule PD-1/PD-L1 inhibitors has lagged far behind, with only a few small-molecule inhibitors entering clinical trials. In addition to antibody drugs and small-molecule inhibitors, reducing the expression levels of PD-L1 has attracted extensive research interest as another promising strategy to target the PD-1/PD-L1 pathway. Herein, we analyze the structures and mechanisms of molecules that reduce PD-L1 expression and classify them as degraders and downregulators according to whether they directly bind to PD-L1. Moreover, we discuss the potential prospects for developing PD-L1-targeting drugs based on these molecules. It is hoped that this perspective will provide profound insights into the discovery of potent antitumor immunity drugs. ■ SIGNIFICANCEReducing PD-L1 expression has been considered as a promising strategy to modulate the PD-1/PD-L1 pathway, which has attracted continuous research interests. This perspective focuses on analyzing the molecules capable of reducing PD-L1 expression and classifies them as degraders and down-regulators according to whether they directly bind to PD-L1. Additionally, it provides deep insights into the rational design strategies and challenges for the development of PD-L1 degraders as well as PD-L1-based combination therapies and multitarget drugs.