最近发现的表观遗传修饰赖氨酸乳酰化 (Kla) 有助于多种癌症的肿瘤发生和进展。除了肿瘤内在作用外，组蛋白乳酰化可能介导肿瘤微环境重塑和免疫逃避。在这里，我们观察到非小细胞肺癌 (NSCLC) 组织中 pan Kla 和 H3K18la 水平升高，这与患者不良预后呈正相关。通过 2-DG 和草酸盐处理中断糖酵解以及 LDHA 和 LDHB 沉默可降低 H3K18la 水平，并通过增强 CD8 T 细胞的细胞毒性来规避 NSCLC 细胞的免疫逃避。从机制上讲，H3K18la 直接激活 POM121 的转录，从而增强 MYC 核转运并直接与 CD274 启动子结合以诱导 PD-L1 表达。在小鼠 NSCLC 异种移植模型中，糖酵解抑制剂和抗 PD-1 抗体的联合治疗诱导瘤内 CD8 T 细胞功能并表现出强大的抗肿瘤功效。总体而言，这项工作揭示了 H3K18la 通过激活 POM121/MYC/PD-L1 通路来增强 NSCLC 细胞的免疫逃逸，这为深入了解翻译后修饰在癌发生中的作用提供了依据，并为开发表观遗传靶向策略提供了理论基础。用于治疗非小细胞肺癌。

The recently discovered epigenetic modification lysine lactylation (Kla) contributes to tumor development and progression in several types of cancer. In addition to the tumor-intrinsic effects, histone lactylation may mediate tumor microenvironment remodeling and immune evasion. Here, we observed elevated pan Kla and H3K18la levels in non-small cell lung cancer (NSCLC) tissues, which was positively correlated with poor patient prognosis. Interruption of glycolysis by 2-DG and oxamate treatment and silencing of LDHA and LDHB reduced H3K18la levels and circumvented immune evasion of NSCLC cells by enhancing CD8+ T cell cytotoxicity. Mechanistically, H3K18la directly activated the transcription of POM121, which enhanced MYC nuclear transport and direct binding to the CD274 promoter to induce PD-L1 expression. In a mouse NSCLC xenograft model, combination therapy with a glycolysis inhibitor and an anti-PD-1 antibody induced intratumoral CD8+ T cell function and exhibited strong anti-tumor efficacy. Overall, this work revealed that H3K18la potentiates the immune escape of NSCLC cells by activating the POM121/MYC/PD-L1 pathway, which offers insight into the role of post-translational modifications in carcinogenesis and provides a rationale for developing an epigenetic-targeted strategy for treating NSCLC.