BACKGROUND: Pancreatic cancer (PC) remains one of the most lethal malignancies with unfavorable prognosis globally. Bioinformatics analysis predicted that SEPP1 was low expressed in PC and related to tumor immune microenvironment, but its biological function was still unclear. METHODS: PC xenograft and liver metastasis mouse models, as well as PC cell-MDSCs co-culture system, were established for in vivo and in vitro studies, respectively. The expression and localization of key molecules were detected by qRT-PCR, western blot, immunohistochemistry and immunofluorescence. Flow cytometry was employed to assess the abundance of immune cells and cell apoptosis. The interactions among KAT8, SEPP1 and LRP8 were detected by co-IP. Cell viability, migration and invasion were monitored by CCK-8 and transwell assays. RESULTS: SEPP1 was downregulated in pancreatic tumors, and it was positively correlated with the abundance of CD8 CONCLUSION: KAT8 catalyzed the acetylation of SEPP1 at K247/249 and modulated the activity of CD8