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

作者：Leisheng Wang, Enhong Chen, Shuo Zhang, Wen Xiang, Hao Ye, Yifei Fu, Shiwei Xu, Qin Wang, Yue Tao, Dongjie Yang, Youzhao He, Shudong Hu, Yong Mao, Hao Hu · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-08156-0 · 被引用次数：8 · 研究领域：RNA modifications and cancer、Lung Cancer Research Studies、Peptidase Inhibition and Analysis

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.