The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000–5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3′UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.

针对 PD-1/PD-L1 的免疫检查点阻断 (ICB) 在治疗癌症方面显示出显着的前景。然而，低反应率和经常观察到的严重副作用限制了其广泛的益处。部分原因是对 PD-L1 的生物学调控了解较少。在这里，我们系统而全面地总结了 PD-L1 从核染色质重组到细胞外呈递的调控。在 PD-L1 和 PD-L2 高表达的癌细胞中，CD274和CD273周围有一个新的 TAD（拓扑相关域）（chr9：5,400,000–5,600,000）被发现，其中包括一种报告的超级增强剂，可驱动 PD-L1 和 PD-L2 的同步转录。重塑的 TAD 允许 STAT3 和 IRF1 等转录因子募集到 PD-L1 基因座，以指导 PD-L1 的表达。转录后，PD-L1 受到 miRNA 和 RNA 结合蛋白通过长 3'UTR 的严格调控。在翻译水平上，PD-L1 蛋白及其膜呈递受到糖基化和泛素化等翻译后修饰的严格调控。此外，PD-L1 可以通过外泌体系统地抑制免疫反应。因此，全面剖析PD-L1/PD-L2的调控，彻底检测PD-L1/PD-L2及其调控网络，将为ICB和基于ICB的联合治疗带来更多见解。