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

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.