2. Academic Validation
  3. AGO2 mediates immunotherapy failure via suppressing tumor IFN-gamma response-dependent CD8+ T cell immunity

AGO2 mediates immunotherapy failure via suppressing tumor IFN-gamma response-dependent CD8+ T cell immunity

  • Cell Rep. 2025 Apr 22;44(4):115445. doi: 10.1016/j.celrep.2025.115445.
Yuzhao Wang 1,  Zibin Chen 1,  Ke Liang 1,  Weikai Wang 2,  Zhihao Hu 2,  Yize Mao 3,  Xiaoyu Liang 4,  Lijuan Jiang 5,  Zhuowei Liu 6,  Zikun Ma 7
Affiliations

Affiliations

  • 1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 2 College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 4 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 5 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: [email protected].
  • 6 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Sun Yat-sen University Cancer Center Gansu Hospital, Lanzhou 730050, China. Electronic address: [email protected].
  • 7 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: [email protected].
PMID: 40106436 DOI: 10.1016/j.celrep.2025.115445
Abstract

Interferon-gamma (IFN-γ), a cytokine essential for activating cellular immune responses, plays a crucial role in Cancer immunosurveillance and the clinical success of immune checkpoint blockade therapy. In this study, we show that Argonaute 2 (AGO2), a key mediator in small RNA-guided gene regulation, inversely correlates with tumor responsiveness to IFN-γ and the efficacy of immunotherapy. Mechanistically, IFN-γ upregulates miR-1246 expression in tumor cells, enhancing its interaction with AGO2. This miR-1246-AGO2 complex disrupts IFN-γ-mediated signal transducer and activator of transcription 1 (STAT1) phosphorylation by stabilizing protein tyrosine Phosphatase non-receptor 6 (PTPN6) mRNA, thereby suppressing the expression of downstream C-X-C motif chemokine ligands (CXCLs), IFN-stimulated genes (ISGs), and human leukocyte antigen (HLA) molecules, which collectively contribute to tumor immune evasion. In preclinical Cancer models, inhibiting AGO2 with BCI-137 or targeting miR-1246 with its antagomir re-sensitizes tumor cells to IFN-γ, leading to the enhanced recruitment, activation, and cytotoxicity of CD8+ T cells and ultimately improving immunotherapy efficacy.

Keywords

AGO2; CD8 T cell; CP: Cancer; CP: Immunology; STAT1; antitumor immunity; bladder cancer; immunotherapy; interferon gamma response; micro-RNA; tumor immune microenvironment.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-119024
    99.84%, Argonaute 2 Inhibitor