H3K18 Lactylation Potentiates Immune Escape of Non-Small Cell Lung Cancer

Abstract 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.