Abstract:Background and Aims Pancreatic cancer is characterized by high aggressiveness and a profoundly immunosuppressive microenvironment, while the mechanisms underlying its immune evasion remain incompletely understood. Enhanced glycolysis in tumor cells leads to excessive lactate accumulation, which can regulate gene transcription through histone lactylation. However, the role of histone lactylation in remodeling the immune microenvironment of pancreatic cancer and its underlying molecular mechanisms remains unclear. This study aimed to investigate the role and molecular mechanism of histone H3 lysine 18 lactylation (H3K18la) in regulating nuclear pore membrane protein 121 (POM121)-mediated immune escape in pancreatic cancer.Methods The expression patterns and prognostic significance of lactate dehydrogenase A (LDHA) and POM121 in pancreatic cancer were analyzed using The Cancer Genome Atlas (TCGA) database. Western blotting was performed to determine the levels of pan-lysine lactylation (Pan-Kla), H3K18la, and POM121 in pancreatic cancer cells. Lactate production was inhibited by treatment with the LDH inhibitor oxamate or by siRNA-mediated LDHA silencing, followed by assessment of intracellular lactate levels, cell proliferation, and colony-forming ability using lactate assays, CCK-8 assays, and colony formation assays. A co-culture system of pancreatic cancer cells and CD8+ T cells was established, and the expression of GZMB, TNF-α, and IFN-γ was analyzed by flow cytometry. ChIP-qPCR and dual-luciferase reporter assays were used to verify the transcriptional regulation of POM121 by H3K18la. Gain- and loss-of-function experiments of POM121 were performed to determine its role in lactylation-mediated immune regulation. A PANC02 tumor-bearing mouse model was established to validate the in vivo effects.Results LDHA and POM121 were significantly upregulated in pancreatic cancer tissues and were associated with poor patient prognosis. Levels of Pan-Kla and H3K18la were markedly increased in pancreatic cancer cells. Oxamate treatment or LDHA silencing reduced intracellular lactate production and H3K18la levels, suppressed pancreatic cancer cell proliferation, and enhanced CD8+ T-cell effector functions, as evidenced by increased expression of GZMB, TNF-α, and IFN-γ. POM121 was highly expressed in pancreatic cancer cells and positively regulated by H3K18la. ChIP-qPCR and dual-luciferase assays demonstrated that H3K18la was enriched at the POM121 promoter region and enhanced its transcriptional activity. Knockdown of POM121 inhibited tumor cell proliferation and enhanced CD8+ T-cell function, whereas POM121 overexpression partially reversed the antitumor immune effects induced by oxamate. In vivo experiments further confirmed that inhibition of lactate production reduced POM121 expression and promoted CD8+ T-cell infiltration, while POM121 overexpression attenuated these effects.Conclusion Lactate generated by glycolytic reprogramming promotes H3K18 lactylation, which transcriptionally activates POM121, thereby suppressing CD8+ T-cell-mediated antitumor immunity and facilitating immune escape in pancreatic cancer. The lactate-H3K18la-POM121 signaling axis may represent a promising therapeutic target for pancreatic cancer immunotherapy.