Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon response via MYC/CDK2/DNMT1 pathway
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...
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60293-4 |
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| author | 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 Dao-xin Ma |
| author_facet | 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 Dao-xin Ma |
| author_sort | Wan-cheng Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c61d0b73f46f4eacb8bd477c49aeb9c9 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c61d0b73f46f4eacb8bd477c49aeb9c92025-08-20T02:30:42ZengNature PortfolioNature Communications2041-17232025-06-0116112110.1038/s41467-025-60293-4Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon response via MYC/CDK2/DNMT1 pathwayWan-cheng Liu0Yi-hong Wei1Jin-feng Chen2Xiang-ling Xing3He-xiao Jia4Xin-yu Yang5Ying-jian Huang6Xiao-min Liu7Ke Xiao8Xiao-dong Guo9Can Can10A-min Zhang11Na He12Hai-lei Zhang13Dao-xin Ma14Department of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversitySuzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of SciencesDepartment of Radiation Oncology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Dermatology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Clinical Laboratory, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityAbstract 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.https://doi.org/10.1038/s41467-025-60293-4 |
| spellingShingle | 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 Dao-xin Ma Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon response via MYC/CDK2/DNMT1 pathway Nature Communications |
| title | Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon response via MYC/CDK2/DNMT1 pathway |
| title_full | Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon response via MYC/CDK2/DNMT1 pathway |
| title_fullStr | Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon response via MYC/CDK2/DNMT1 pathway |
| title_full_unstemmed | Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon response via MYC/CDK2/DNMT1 pathway |
| title_short | Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon response via MYC/CDK2/DNMT1 pathway |
| title_sort | inhibition of tumor intrinsic nat10 enhances antitumor immunity by triggering type i interferon response via myc cdk2 dnmt1 pathway |
| url | https://doi.org/10.1038/s41467-025-60293-4 |
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