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tRNA m1A modification orchestrates STING translation in macrophages to enhance antitumor immunity and CAR-macrophage immunotherapy

Cellular & Molecular Immunology volume 23, pages 261–272 (2026)Cite this article

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Abstract

Tumor-associated macrophages (TAMs) play crucial roles in tumor progression. However, the mechanisms underlying the posttranscriptional regulation of TAMs remain largely unknown. Here, we demonstrated that Trmt61a, the "writer" enzyme of tRNA N1-methyladenosine (m1A) modification, is highly expressed in proinflammatory macrophages in tumor microenvironment. We generated conditional knockout (KO) mice for Trmt61a and observed that Trmt61a deletion in macrophages significantly promoted tumor growth. Mechanistically, we identified that m1A maintains the translation of STING, enhances STING-TBK1-IFN-β signaling in macrophages and therefore suppresses tumor cell growth. We further generated TRMT61A-overexpressing human iPSC-derived CAR-macrophage and demonstrated that human TRMT61A effectively promoted antitumor CAR-macrophage therapy in vivo. Collectively, our findings reveal a novel regulatory mechanism of tRNA m1A modification in macrophages, highlighting the antitumor therapeutic potential of targeting tRNA m1A modification in macrophages.

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Acknowledgements

We thank K. Mao, M. Yang, and J. Zhao for their technical and administrative assistance and all other members of the Hua-Bing Li laboratory for their discussions and comments. This work was supported by the National Natural Science Foundation of China (82341017/82541015/82441048/82461160323/82325024/82350112 to H.-B.L., 32400747 to X. W.), the National Key R&D Plan of China (2025YFC3410100 to H-B.L.), the Ministry of Science and Technology of China (2021YFA1100800 to H-B.L.), the Chongqing Municipal Science and Technology Bureau (CSTB2025TIAD-STX0043/CSTB2025TIAD-STX0045), the Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJZD-M202500402), the Chongqing Municipal Finance Bureau and Chongqing Municipal Education Commission (010405000001), the Chongqing Science and Technology Bureau (CSTB2025YCJH-KYXM0002). We thank Ning Xu and Yue Yin of the mass spectrometry system at the National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, Chinese Academy of Science, China, for MS sample preparation, data collection and data analysis.

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Author notes

  1. These authors contributed equally: Xuefei Wang, Xudong Wang, Hao Li.

Authors and Affiliations

  1. Department of Geriatrics, Medical Center on Aging of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Xuefei Wang, Weiguo Hu & Hua-Bing Li

  2. Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Xuefei Wang, Huifang Chen, Xueming Cai, Bin Li, Youqiong Ye & Hua-Bing Li

  3. Liangzhu Laboratory, Zhejiang University, Hangzhou, 311121, China

    Xudong Wang, Siyu Su & Jin Zhang

  4. Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Xudong Wang, Siyu Su & Jin Zhang

  5. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Hao Li & Rujuan Liu

  6. Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China

    Shuyu Liu & Xiangjia Zhu

  7. National Health Center Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, 200031, China

    Shuyu Liu & Xiangjia Zhu

  8. Chongqing International Institute for Immunology, Chongqing, 401320, China

    Yang Lu & Hua-Bing Li

  9. Institute of Hematology, Hangzhou, 310058, China

    Jin Zhang

  10. Center of Gene/Cell Engineering and Genome Medicine of Zhejiang Province, Hangzhou, 310000, China

    Jin Zhang

  11. Shanghai Jiao Tong University School of Medicine - Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Hua-Bing Li

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  1. Xuefei Wang
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Contributions

H-B.L. and X.W. conceived the project, designed the research and wrote the manuscript. X.W. designed and performed the experiments, analyzed and interpreted the data, and drafted the manuscript. X.W. and S.S. performed the CAR-iMAC experiments. H.L. performed and analyzed the mass spectrometry data and tRNA-seq data. S.L. and Y.L. performed part of the tumor model and Western blotting experiments. H.C. and Y.Y. helped with the analysis of the scRNA-seq, bulk RNA-seq and ChIP-seq data. B.L., R.L., W.H., X.Z. and Y.Y. contributed to the discussion and suggestions. This study was supervised by H-B.L. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Weiguo Hu, Xiangjia Zhu, Jin Zhang, Youqiong Ye or Hua-Bing Li.

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The authors declare that they have no competing interests. B.L. is an editorial board member of Cellular & Molecular Immunology, but he has not been involved in the peer review or the decision-making of the article.

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Wang, X., Wang, X., Li, H. et al. tRNA m1A modification orchestrates STING translation in macrophages to enhance antitumor immunity and CAR-macrophage immunotherapy. Cell Mol Immunol 23, 261–272 (2026). https://doi.org/10.1038/s41423-025-01383-7

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