Beyond inhibition against the PD-1/PD-L1 pathway: development of PD-L1 inhibitors targeting internalization and degradation of PD-L1

Tumor cells hijack the programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway to suppress the immune response through overexpressing PD-L1 to interact with PD-1 of T cells. With in-depth ongoing research, tumor-intrinsic PD-L1 is found to play important roles in tumor progression without interaction with PD-1 expressed on T cells, which provides an additional important target and therapeutic approach for development of PD-L1 inhibitors. Existing monoclonal antibody (mAb) drugs against the PD-1/PD-L1 pathway generally behave by conformationally blocking the interactions of PD-1 with PD-L1 on the cell surface. Beyond general inhibition of the protein-protein interaction (PPI), inhibitors targeting PD-L1 currently focus on the functional inhibition of the interaction between PD-1/PD-L1 and degradation of tumor-intrinsic PD-L1. This perspective will clarify the evolution of PD-L1 inhibitors and provide insights into the current development of PD-L1 inhibitors, especially targeting internalization and degradation of PD-L1.