Regulation of PD-1 and PD-L1 expression in tumor immune microenvironment

Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) constitute a core immune checkpoint axis that restrains T cell activation. Under physiological conditions, the interaction between PD-1 and PD-L1 maintains peripheral tolerance and prevents tissue damage from excessive immune responses. In tumor microenvironment, this axis is frequently activated through upregulation of PD-L1 on cancer cells, causing T cell dysfunction and tumor immune escape. PD-1/PD-L1 blockades reactivate exhausted T cells to kill cancer cells. However, some cancer patients fail to respond to PD-1/PD-L1 inhibitors, and the underlying mechanisms remain incompletely revealed. Thus, it is important to unveil the regulatory mechanisms that govern PD-1 and PD-L1 expression in tumor microenvironment. This review systematically summarizes the regulation of PD-1/PD-L1 expression at the genetic, epigenetic, transcriptional, and posttranscriptional levels. Beyond expression levels, posttranslational modifications and membrane trafficking determine PD‑L1 surface availability and sensitivity to PD-1/PD-L1 inhibitors. In this review, the rapidly expanding clinical trials of PD-1/PD-L1 blockades and future research directions are also discussed.