Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling

Wenjie Wei; Hongzhao Li; Shuo Tian; Chi Zhang; Junxiao Liu; Wen Tao; Tianwei Cai; Yuhao Dong; Chuang Wang; Dingyi Lu; Yakun Ai; Wanlin Zhang; Hanfeng Wang; Kan Liu; Yang Fan; Yu Gao; Qingbo Huang; Xin Ma; Baojun Wang; Xu Zhang; Yan Huang

doi:10.1172/JCI186648

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Wei, W. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Li, H. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Tian, S. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Zhang, C. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Liu, J. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Tao, W. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Cai, T. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Dong, Y. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Wang, C. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Lu, D. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Ai, Y. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Zhang, W. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Wang, H. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Liu, K. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Fan, Y. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Gao, Y. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Huang, Q. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Ma, X. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Wang, B. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Zhang, X. in: JCI | PubMed | Google Scholar

¹Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

²State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

³Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

Find articles by Huang, Y. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI186648.
Copyright © 2025, Wei et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published February 18, 2025 - Version history

Tumor cells often employ many ways to restrain type I interferon signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulate this process remains unclear and its effects on antitumor immunity are relatively unexplored. Here, we find that asparagine inhibits IFN-I signaling and promotes immune escape in bladder cancer. Depletion of asparagine synthetase (ASNS) strongly limits in vivo tumor growth in a CD8+ T cell-dependent manner and boosts immunotherapy efficacy. Moreover, clinically approved ASNase synergizes with anti-PD-1 therapy in suppressing tumor growth. Mechanistically, asparagine can directly bind to RIG-I and facilitate CBL-mediated RIG-I degradation, thereby suppressing IFN signaling and antitumor immune responses. Clinically, tumors with higher ASNS expression show decreased responsiveness to ICIs therapy. Together, our findings uncover asparagine as a natural metabolite to modulate RIG-I-mediated IFN-I signaling, providing the basis for developing the combinatorial use of ASNase and anti-PD-1 for bladder cancer.

Version 1 (February 18, 2025): In-Press Preview

Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling

Wenjie Wei,¹ Hongzhao Li,¹ Shuo Tian,¹ Chi Zhang,¹ Junxiao Liu,¹ Wen Tao,¹ Tianwei Cai,¹ Yuhao Dong,¹ Chuang Wang,¹ Dingyi Lu,² Yakun Ai,³ Wanlin Zhang,³ Hanfeng Wang,¹ Kan Liu,¹ Yang Fan,¹ Yu Gao,¹ Qingbo Huang,¹ Xin Ma,¹ Baojun Wang,¹ Xu Zhang,¹ and Yan Huang¹

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Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling

Wenjie Wei,1 Hongzhao Li,1 Shuo Tian,1 Chi Zhang,1 Junxiao Liu,1 Wen Tao,1 Tianwei Cai,1 Yuhao Dong,1 Chuang Wang,1 Dingyi Lu,2 Yakun Ai,3 Wanlin Zhang,3 Hanfeng Wang,1 Kan Liu,1 Yang Fan,1 Yu Gao,1 Qingbo Huang,1 Xin Ma,1 Baojun Wang,1 Xu Zhang,1 and Yan Huang1

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Wenjie Wei,¹ Hongzhao Li,¹ Shuo Tian,¹ Chi Zhang,¹ Junxiao Liu,¹ Wen Tao,¹ Tianwei Cai,¹ Yuhao Dong,¹ Chuang Wang,¹ Dingyi Lu,² Yakun Ai,³ Wanlin Zhang,³ Hanfeng Wang,¹ Kan Liu,¹ Yang Fan,¹ Yu Gao,¹ Qingbo Huang,¹ Xin Ma,¹ Baojun Wang,¹ Xu Zhang,¹ and Yan Huang¹