The emerging roles of PD-L1 subcellular localization in tumor immune evasion

Targeting immune checkpoint PD-1 or its ligand PD-L1 blockade has achieved a great therapeutic effect in a variety of cancer types. However, the overall response rate and duration are still limited for intrinsic and acquired resistance. There is an urgent need to understand the underlying mechanism. Studies showed that PD-L1 regulation is related to the response to PD-1 monoclonal antibodies (PD-1 mAB). Interestingly, emerging studies found that the different distribution of PD-L1 has distinct functions in tumor through the specific signaling pathways. Thus, controlling the distribution of PD-L1 provides an attractive therapeutic strategy for enhancing PD-1 mAB efficiency and rewiring the resistance. Here, we review the recent studies about the role and regulation of PD-L1 distribution from synthesis to surface delivery, internalization, recycling, or lysosome degradation and translocated into the nucleus or secreted into the extracellular space. We place this knowledge in the context of observations in the clinic and discuss the potential therapeutic strategies to enhance the efficacy of anti-PD-1/PD-L1 therapy.