Activation of CD8+ T cells necessitates rapid metabolic reprogramming to fulfill the substantial biosynthetic demands of effector functions. However, the posttranscriptional mechanisms underpinning this process remain obscure. The transfer RNA (tRNA) N1-methyladenine (m1A) modification, essential for tRNA stability and protein translation, has an undefined physiological function in CD8+ T cells, particularly in antitumor responses. Here, we demonstrate that the tRNA m1A “writer” gene Trmt61a enhances the tumor-killing capacity of CD8+ T cells by regulating cholesterol biosynthesis. Deletion of Trmt61a in CD8+ T cells leads to a compromised tumor-killing function in both in vivo and in vitro assays. Mechanistically, tRNA m1A promotes antitumor immunity in CD8+ T cells by enhancing the translation of ATP citrate lyase, a key enzyme for cholesterol biosynthesis. Cholesterol supplementation rescues the impaired tumor-killing function and proliferation of TRMT61A-deficient CD8+ T cells. Our findings highlight tRNA m1A modification as a regulatory checkpoint in cholesterol metabolism in CD8+ T cells, suggesting potential novel strategies for cancer immunotherapy.
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January 28 2025
tRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells
Shan Miao
,
Shan Miao
*
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
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Hao Li
,
Hao Li
*
(Methodology)
3
School of Life Science and Technology, ShanghaiTech University
, Shanghai, China
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Xiaohan Song
,
Xiaohan Song
*
(Data curation, Formal analysis, Visualization, Writing - review & editing)
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
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Yongbo Liu
,
Yongbo Liu
(Conceptualization, Investigation, Validation)
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
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Gaoyang Wang
,
Gaoyang Wang
(Data curation, Formal analysis, Software, Visualization)
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
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Chen Kan
,
Chen Kan
(Data curation)
4
School of Biological Science, The University of Manchester
, Manchester, UK
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Youqiong Ye
,
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
Youqiong Ye: [email protected]
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Ru-Juan Liu
,
3
School of Life Science and Technology, ShanghaiTech University
, Shanghai, China
Ru-Juan Liu: [email protected]
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Hua-Bing Li
(Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing)
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
5
Chongqing International Institute for Immunology
, Chongqing, China
6
Institute of Immunological Innovation and Translation, Chongqing Medical University
, Chongqing, China
7Department of Geriatrics,
Medical Center on Aging of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
Correspondence to Hua-Bing Li: [email protected]
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Shan Miao
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing
*
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
3
School of Life Science and Technology, ShanghaiTech University
, Shanghai, China
Xiaohan Song
Data curation, Formal analysis, Visualization, Writing - review & editing
*
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
Yongbo Liu
Conceptualization, Investigation, Validation
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
Gaoyang Wang
Data curation, Formal analysis, Software, Visualization
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
Chen Kan
Data curation
4
School of Biological Science, The University of Manchester
, Manchester, UK
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
3
School of Life Science and Technology, ShanghaiTech University
, Shanghai, China
Hua-Bing Li
Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing
1
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
2
Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
5
Chongqing International Institute for Immunology
, Chongqing, China
6
Institute of Immunological Innovation and Translation, Chongqing Medical University
, Chongqing, China
7Department of Geriatrics,
Medical Center on Aging of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
Correspondence to Hua-Bing Li: [email protected]
Ru-Juan Liu: [email protected]
Youqiong Ye: [email protected]
*
S. Miao, H. Li, and X. Song contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
April 10 2024
Revision Received:
September 13 2024
Accepted:
December 11 2024
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funding
Funder(s):
Ministry of Science and Technology of China
- Award Id(s): 2021YFA1100800,2020YFA0803400
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 82325024/82341017/82350112/82030042/32070917
Funder(s):
Chongqing International Institute for Immunology
- Award Id(s): 2023YJC01
Funder(s):
Shanghai Municipal Health Commission
- Award Id(s): 2022JC001/2022XD047
Funder(s):
Innovative Research Team of High-Level Local Universities in Shanghai
- Award Id(s): SHSMU-ZDCX20212501
© 2025 Miao et al.
2025
Miao et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Exp Med (2025) 222 (3): e20240559.
Article history
Received:
April 10 2024
Revision Received:
September 13 2024
Accepted:
December 11 2024
Citation
Shan Miao, Hao Li, Xiaohan Song, Yongbo Liu, Gaoyang Wang, Chen Kan, Youqiong Ye, Ru-Juan Liu, Hua-Bing Li; tRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells. J Exp Med 3 March 2025; 222 (3): e20240559. doi: https://doi.org/10.1084/jem.20240559
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