FIG. 6.

Schematic diagram of the regulation of PD‐1/PD‐L1 signaling by CMTM4 in liver cancer. CMTM4 physically interacts with PD‐L1 in tumor cells to promote and sustain PD‐L1 expression at the plasma membrane by shuttling PD‐L1 to recycling endosomes, preventing it from being degraded by the lysosome or proteasome. As a result, CMTM4 potentiates the binding of PD‐L1 on tumor cells to PD‐1 on T cells, inhibiting T‐cell activation and facilitating immune escape. Inhibition of proteasomal activity by MG132 and inhibition of clathrin‐dependent endocytosis by Dyngo4a restored PD‐L1 surface expression after CMTM4 inhibition. Abbreviations: EE, early endosome; RE, recycling endosome; MHC‐Ag, MHC class I conjugated with tumor antigen; TCR, T‐cell receptor; U, ubiquitin.