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

Tumor cells often employ many ways to restrain type I IFN signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulates this process remains unclear, and its effects on antitumor immunity are relatively unexplored. Here, we found that asparagine inhibited IFN-I signaling and promoted immune escape in bladder cancer. Depletion of asparagine synthetase (ASNS) strongly limited in vivo tumor growth in a CD8+ T cell-dependent manner and boosted immunotherapy efficacy. Moreover, clinically approved L-asparaginase (ASNase),synergized 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 immune checkpoint inhibitor 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.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-02-18
DOI
https://doi.org/10.1172/jci186648
Citations
10
Primary Topic
Eicosanoids and Hypertension Pharmacology
Type
article
Field-Weighted Citation Impact
11.12
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article

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

Hongzhao Li, Junxiao Liu, Shuo Tian, Yu Gao et al.
10 citations
Journal of Clinical Investigation
Eicosanoids and Hypertension Pharmacology
11.12
article

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

Hongzhao Li, Junxiao Liu, Shuo Tian, Yu Gao, Fan Yang, Dingyi Lu, Tianwei Cai, Yan Huang, Xu Dong Zhang, Qingbo Huang, Chuang Wang, Chi Zhang, Kan Liu, Tao Wen, Xin Ma, Yu Dong, Yanqiu Ai, Wenjie Wei, Hanfeng Wang, Baojun Wang, Wanlin Zhang
article en
10 citations

Abstract

Tumor cells often employ many ways to restrain type I IFN signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulates this process remains unclear, and its effects on antitumor immunity are relatively unexplored. Here, we found that asparagine inhibited IFN-I signaling and promoted immune escape in bladder cancer. Depletion of asparagine synthetase (ASNS) strongly limited in vivo tumor growth in a CD8+ T cell-dependent manner and boosted immunotherapy efficacy. Moreover, clinically approved L-asparaginase (ASNase),synergized 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 immune checkpoint inhibitor 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.

Journal of Clinical InvestigationVol. 135(8)
Chinese PLA General Hospital (CN), National Center of Biomedical Analysis (CN), PLA Academy of Military Science (CN)
Zero hunger
Openalex Percentile: Top 2%
Eicosanoids and Hypertension Pharmacology
11.12
DOIOpen Access PDFOpenAlex
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