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Peer-reviewedCC BYThe Journal of clinical investigation

Targeting N-acetyltransferase 10 reprograms Treg function to enhance anti-PD-1 immunotherapy sensitivity in murine lung tumors.

  • Xuewei Qi1
  • Dan Cui2
  • Xiao Li3
  • Wenfan Fu4
  • Handong Ma1
  • Wenting Guo5
  • Jiabao Wang1
  • Jiaxi Song1
  • Jiaxin Ma1
  • Jing Yang1
  • Haoyu Yu1
  • Yuting Hong1
11 more authors
  • Qian Wang6
  • Susu Luo7
  • Jia Wang7
  • Baixing Wu5
  • Shanshan Li3
  • Hao Cheng8
  • Min Cheng9
  • Bin Li8
  • Kaiming Zhang3
  • Jia Li2,10
  • Fengyin Li1,11
11 affiliations
  1. 1State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  2. 2Guangzhou National Laboratory, Xing Dao Huan Bei Road, Guangzhou International Bio Island, Guangzhou, China.
  3. 3Ministry of Education Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of Institute of Health and Medicine (IHM), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  4. 4Department of Chest Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.
  5. 5Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  6. 6Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.
  7. 7Guangzhou Medical University–Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, China.
  8. 8Center for Immune-related Disease at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  9. 9Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  10. 10State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  11. 11Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
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Abstract

A significant challenge for improving the efficacy of immune checkpoint blockade (ICB) therapy is the concurrent activation of Tregs, which can dampen antitumor responses. Thus, elucidating the mechanisms that maintain Treg-suppressive function within the tumor microenvironment is critical. Here, we identified an accumulation of N-acetyltransferase 10-modified (NAT10-modified) RNA, particularly in NAT10+FOXP3+ Tregs, in human non-small cell lung cancer. Genetic ablation of Nat10 in tumor-infiltrating (TI) Tregs, or pharmacological inhibition of NAT10 expression, significantly reduced the PD-1+ Treg/CD8+ T cell ratio. These effects were accompanied by an increase in IFN-γ+ Tregs, a reduction in the immunosuppressive activity of Tregs, and inhibition of tumor progression. Mechanistically, NAT10 promotes TI Treg infiltration and activation independently of its RNA-modifying function by directly interacting with FOXP3 and chromatin, modulating local 3D chromatin contacts. Combined administration of anti-PD-1 antibodies and a NAT10 inhibitor further impaired TI Treg-mediated immunosuppression, leading to enhanced tumor control. Our findings demonstrate that NAT10 is a key regulator of TI Treg fragility and function and that its inhibition may enhance the therapeutic efficacy of ICB.

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Cite

BibTeXRIS
BibTeX
@article{qi2026targeting,
  title = {{Targeting N-acetyltransferase 10 reprograms Treg function to enhance anti-PD-1 immunotherapy sensitivity in murine lung tumors.}},
  author = {Xuewei Qi and Dan Cui and Xiao Li and Wenfan Fu and Handong Ma and Wenting Guo and Jiabao Wang and Jiaxi Song and Jiaxin Ma and Jing Yang and Haoyu Yu and Yuting Hong and Qian Wang and Susu Luo and Jia Wang and Baixing Wu and Shanshan Li and Hao Cheng and Min Cheng and Bin Li and Kaiming Zhang and Jia Li and Fengyin Li},
  journal = {The Journal of clinical investigation},
  year = {2026},
  month = nov,
  doi = {10.1172/jci189034},
  url = {https://europepmc.org/article/MED/42969236},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Targeting N-acetyltransferase 10 reprograms Treg function to enhance anti-PD-1 immunotherapy sensitivity in murine lung tumors.
AU  - Xuewei Qi
AU  - Dan Cui
AU  - Xiao Li
AU  - Wenfan Fu
AU  - Handong Ma
AU  - Wenting Guo
AU  - Jiabao Wang
AU  - Jiaxi Song
AU  - Jiaxin Ma
AU  - Jing Yang
AU  - Haoyu Yu
AU  - Yuting Hong
AU  - Qian Wang
AU  - Susu Luo
AU  - Jia Wang
AU  - Baixing Wu
AU  - Shanshan Li
AU  - Hao Cheng
AU  - Min Cheng
AU  - Bin Li
AU  - Kaiming Zhang
AU  - Jia Li
AU  - Fengyin Li
PY  - 2026
DA  - 2026/11/02
JO  - The Journal of clinical investigation
DO  - 10.1172/jci189034
UR  - https://europepmc.org/article/MED/42969236
AB  - A significant challenge for improving the efficacy of immune checkpoint blockade (ICB) therapy is the concurrent activation of Tregs, which can dampen antitumor responses. Thus, elucidating the mechanisms that maintain Treg-suppressive function within the tumor microenvironment is critical. Here, we identified an accumulation of N-acetyltransferase 10-modified (NAT10-modified) RNA, particularly in NAT10+FOXP3+ Tregs, in human non-small cell lung cancer. Genetic ablation of Nat10 in tumor-infiltrating (TI) Tregs, or pharmacological inhibition of NAT10 expression, significantly reduced the PD-1+ Treg/CD8+ T cell ratio. These effects were accompanied by an increase in IFN-γ+ Tregs, a reduction in the immunosuppressive activity of Tregs, and inhibition of tumor progression. Mechanistically, NAT10 promotes TI Treg infiltration and activation independently of its RNA-modifying function by directly interacting with FOXP3 and chromatin, modulating local 3D chromatin contacts. Combined administration of anti-PD-1 antibodies and a NAT10 inhibitor further impaired TI Treg-mediated immunosuppression, leading to enhanced tumor control. Our findings demonstrate that NAT10 is a key regulator of TI Treg fragility and function and that its inhibition may enhance the therapeutic efficacy of ICB.
SN  - 0021-9738
SN  - 1558-8238
ER  -