Antagonistic antibodies targeting the inhibitory immune-checkpoint receptor PD-1 or its ligand PD-L1 are used to treat a wide range of cancer types and can substantially improve patient survival. Nevertheless, strategies to overcome intrinsic and acquired resistance are required to respectively increase response rates and durations. PD-L1 is often upregulated in various malignancies, and emerging evidence suggests numerous underlying mechanisms involving distinct oncogenic signalling pathways. Thus, specific small-molecule inhibitors have the potential to simultaneously suppress not only a key oncogenic signalling pathway but also PD-L1 expression and/or activity in particular cancers, thereby presenting attractive candidate drugs for combination with existing immune-checkpoint inhibitors and/or other targeted agents. Herein, we summarize advances in understanding the mechanisms regulating PD-L1 expression at the transcriptional, post-transcriptional, translational and post-translational levels in cancers. We describe the roles of the diverse post-translational modifications of PD-L1, including phosphorylation, palmitoylation, glycosylation, acetylation and ubiquitination. Moreover, we discuss the potential use of small-molecule agents to modulate these mechanisms as well as of predictive biomarkers to stratify patients for optimal treatment, and provide our perspective on potential therapeutic strategies to circumvent resistance to conventional anti-PD-1/PD-L1 antibodies.

靶向抑制性免疫检查点受体 PD-1 或​​其配体 PD-L1 的拮抗抗体用于治疗多种癌症类型，可显着提高患者生存率。然而，需要克服内在和获得性抵抗的策略来分别增加响应率和持续时间。PD-L1 通常在各种恶性肿瘤中上调，新出现的证据表明存在许多涉及不同致癌信号通路的潜在机制。因此，特定的小分子抑制剂不仅有可能同时抑制关键的致癌信号通路，而且还能抑制特定癌症中的 PD-L1 表达和/或活性，从而为与现有免疫检查点抑制剂和/或联合应用提供有吸引力的候选药物。其他目标代理。在此处，我们总结了在癌症的转录、转录后、翻译和翻译后水平调节 PD-L1 表达的机制方面的进展。我们描述了 PD-L1 的多种翻译后修饰的作用，包括磷酸化、棕榈酰化、糖基化、乙酰化和泛素化。此外，我们讨论了小分子药物调节这些机制的潜在用途，以及预测性生物标志物对患者进行分层以获得最佳治疗的潜在用途，并提供我们对潜在治疗策略的看法，以规避对常规抗 PD-1/PD- 的耐药性。 L1 抗体。我们描述了 PD-L1 的多种翻译后修饰的作用，包括磷酸化、棕榈酰化、糖基化、乙酰化和泛素化。此外，我们讨论了小分子药物调节这些机制的潜在用途，以及预测性生物标志物对患者进行分层以获得最佳治疗的潜在用途，并提供我们对潜在治疗策略的看法，以规避对常规抗 PD-1/PD- 的耐药性。 L1 抗体。我们描述了 PD-L1 的多种翻译后修饰的作用，包括磷酸化、棕榈酰化、糖基化、乙酰化和泛素化。此外，我们讨论了小分子药物调节这些机制的潜在用途，以及预测性生物标志物对患者进行分层以获得最佳治疗的潜在用途，并提供我们对潜在治疗策略的看法，以规避对常规抗 PD-1/PD- 的耐药性。 L1 抗体。