Immunotherapies targeting the PD-1/PD-L1 axis have become first-line treatments in multiple cancers. However, only a limited subset of individuals achieves durable benefits because of the elusive mechanisms regulating PD-1/PD-L1. Here, we report that in cells exposed to interferon-γ (IFNγ), KAT8 undergoes phase separation with induced IRF1 and forms biomolecular condensates to upregulate PD-L1. Multivalency from both the specific and promiscuous interactions between IRF1 and KAT8 is required for condensate formation. KAT8–IRF1 condensation promotes IRF1 K78 acetylation and binding to the CD247 (PD-L1) promoter and further enriches the transcription apparatus to promote transcription of PD-L1 mRNA. Based on the mechanism of KAT8–IRF1 condensate formation, we identified the 2142–R8 blocking peptide, which disrupts KAT8–IRF1 condensate formation and consequently inhibits PD-L1 expression and enhances antitumor immunity in vitro and in vivo. Our findings reveal a key role of KAT8–IRF1 condensates in PD-L1 regulation and provide a competitive peptide to enhance antitumor immune responses.

针对 PD-1/PD-L1 轴的免疫疗法已成为多种癌症的一线治疗方法。然而，由于难以捉摸的 PD-1/PD-L1 调节机制，只有一小部分人能够获得持久的益处。在这里，我们报告在暴露于干扰素-γ (IFNγ) 的细胞中，KAT8 与诱导的 IRF1 发生相分离并形成生物分子凝聚物以上调 PD-L1。IRF1 和 KAT8 之间特定和混杂相互作用的多价性是冷凝物形成所必需的。KAT8–IRF1 缩合促进 IRF1 K78 乙酰化并与CD247结合(PD-L1) 启动子并进一步丰富转录装置以促进 PD-L1 mRNA 的转录。基于 KAT8-IRF1 凝聚物形成的机制，我们鉴定了 2142-R8 阻断肽，它可以破坏 KAT8-IRF1 凝聚物的形成，从而抑制 PD-L1 表达并增强体外和体内的抗肿瘤免疫力。我们的研究结果揭示了 KAT8–IRF1 缩合物在 PD-L1 调节中的关键作用，并提供了一种竞争性肽来增强抗肿瘤免疫反应。