2. Academic Validation
  3. Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling

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

  • J Clin Invest. 2025 Feb 18:e186648. doi: 10.1172/JCI186648.
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,  Yan Huang 1
Affiliations

Affiliations

  • 1 Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China.
  • 2 State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
  • 3 Department of Pathology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China.
PMID: 39964752 DOI: 10.1172/JCI186648
Abstract

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.

Keywords

Cell biology; Immunology; Immunotherapy; Therapeutics; Urology.

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