Targeting the ac4C ‘Writer’ NAT10 enhances pancreatic cancer immunotherapy via dual modulation of CD8+ T cells and tumor cells

Pancreatic cancer (PC) is highly lethal because of its immunosuppressive tumor microenvironment and resistance to immunotherapy. This study explored the role of NAT10-mediated N4-acetylcytidine (ac4C) RNA modification in pancreatic cancer progression and immune evasion. NAT10 (N-acetyltransferase 10) is overexpressed in pancreatic cancer tissues and correlates with poor prognosis. Mechanistically, NAT10 stabilizes ETS2 mRNA through ac4C acetylation, forming a positive feedback loop that upregulates NAT10 and PD-L1, thereby suppressing CD8 + T cell infiltration and promoting immune evasion. In addition, NAT10 stabilizes KRT8 mRNA via ac4C acetylation, which drives cancer cell proliferation and metastasis. Single-cell RNA sequencing analysis revealed enhanced interactions between pancreatic cancer epithelial cells with high NAT10 and KRT8 expression, and T cells, thereby providing new insights into the immune microenvironment. In vivo, NAT10 knockdown significantly inhibited tumor growth, enhanced CD8 + T cell infiltration, and reduced lung metastasis. Notably, combination therapy with an NAT10 inhibitor and anti-PD-L1 antibody demonstrated superior antitumor efficacy compared to monotherapy. In conclusion, NAT10 promotes pancreatic cancer progression and immune evasion by regulating the ETS2-PD-L1 axis and stabilizing KRT8 mRNA, highlighting its potential as a therapeutic target for overcoming immunotherapy resistance.