Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon response via MYC/CDK2/DNMT1 pathway

Wan-cheng Liu, Yi-hong Wei, Jin-feng Chen, Xiang-ling Xing, He-xiao Jia, Xin-yu Yang, Ying-jian Huang, Xiao-min Liu, Ke Xiao, Xiao-dong Guo, Can Can, A-min Zhang, Na He, Hai-lei Zhang and Dao-xin Ma ()
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Wan-cheng Liu: Qilu Hospital of Shandong University
Yi-hong Wei: Qilu Hospital of Shandong University
Jin-feng Chen: Chinese Academy of Sciences
Xiang-ling Xing: Qilu Hospital of Shandong University
He-xiao Jia: Qilu Hospital of Shandong University
Xin-yu Yang: Qilu Hospital of Shandong University
Ying-jian Huang: Qilu Hospital of Shandong University
Xiao-min Liu: Qilu Hospital of Shandong University
Ke Xiao: Qilu Hospital of Shandong University
Xiao-dong Guo: Qilu Hospital of Shandong University
Can Can: Qilu Hospital of Shandong University
A-min Zhang: Qilu Hospital of Shandong University
Na He: Qilu Hospital of Shandong University
Hai-lei Zhang: Qilu Hospital of Shandong University
Dao-xin Ma: Qilu Hospital of Shandong University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Posttranscriptional modifications are involved in cancer progression. However, the function and regulatory mechanism of mRNA acetylation modification remains largely unknown. Here, we discover an unexpected role of N4-acetylcytidine (ac4C) RNA acetyltransferase NAT10 in reshaping the tumor immune microenvironment. By analyzing patients’ data, we find that NAT10 is upregulated in tumor tissues, and negatively correlated with immune cell infiltration and overall survival. Loss of tumoral NAT10 enhances tumor-specific cellular immune response and suppresses tumor growth. Mechanistically, MYC is identified as a key downstream target of NAT10 via enhancing mRNA ac4C modification. Inhibition of NAT10 blocks the MYC/CDK2/DNMT1 pathway, enhances double-stranded RNA (dsRNA) formation, which triggers type I interferon response and improves tumor specific CD8+ T cell response in vivo. More importantly, the inhibition of NAT10, using either small molecule inhibitor (Remodelin) or PEI/PC7A/siNAT10 nanoparticles, synergize PD-1 blockade in elevating anti-tumor immune response and repressing tumor progression. Our findings thus uncover the crucial role of tumor-intrinsic NAT10 in tumor immune microenvironment, which represents a promising target for enhancing cancer immunotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-60293-4

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