Fig. 3

Overexpression of PD-L1 in hypoxic cells and the mechanism of the PD-1/PD-L1 signalling pathway. Hypoxia can contribute both directly and indirectly to the upregulation of transcription factors, including HIF-1α, NF-κB, and STAT3, which act on the promoter of PD-L1 to regulate its expression. At the same time, the cytokines released by hypoxic cells or immune cells can stimulate the expression of PD-L1. In hypoxic cells, extracellular vesicles transporting PD-L1 on their surface are released. Mechanistically, the PD-1–PD-L1 complex modulates immune dysfunction by binding to TCRs and momentarily associating with the phosphatase SHP2. This results in the dephosphorylation of proximal TCR signalling molecules, such as ZAP70, and the decreased phosphorylation of TCR downstream signalling molecules like PLCγ1 and PKCtheta, similar to the role that inhibition of the PI3K/Akt pathway plays in these processes. Therefore, PD-1–PD-L1 binding affects the activation, proliferation, differentiation, metabolism, and IL-2 production of T cells. Furthermore, the PD-1/PD-L1 pathway promotes differentiation and development, sustaining the function of regulatory T cells by enhancing Foxp3 expression, inhibiting the Akt/mTOR signalling pathway, and attenuating the phosphorylation of ERK2. And the activation of Tregs participate in the PD-1–PD-L1 axis-mediated NK cells dysfunction. Abbreviations: PD-L1 programmed death-ligand 1, PD-1 programmed cell death protein 1, HIF-1α hypoxia-inducible factor 1 alpha, NF-κB nuclear factor kappa B, STAT3 signal transducer and activation of transcription-3, TCR T cell receptor, SHP2 Src homology 2 domain-containing tyrosine phosphatase 2, ZAP70 zeta chain of T cell receptor-associated protein kinase 70, PLCγ1 phospholipase C gamma 1, PKCtheta protein kinase C theta, PI3K phosphoinositide 3-kinase, AKT protein kinase B, IL-2 interleukin 2, mTOR mechanistic target of rapamycin, ERK2 extracellular signal-regulated kinase 2, Treg regulatory T