Work

Targeting alanyl-tRNA synthetase 1 unlocks antitumor immunity by inducing type I interferon signaling in ovarian cancer

Year: 2026

Type: article

Abstract: Ovarian cancer is a leading cause of gynecological cancer-related mortality, with its immunosuppressive tumor microenvironment (TME) limiting the effectiveness of immune checkpoint inhibitor therapy. Alanyl-tRNA synthetase 1 (AARS1) expression in ovarian cancer has been linked to poor prognosis; however, its immunological role remains unclear. In this study, we generated an Aars1-knockdown ID8 syngeneic mouse model to evaluate the role of AARS1 in vivo. Immune infiltration was assessed using flow cytometry and immunohistochemistry. Multi-omics profiling, including single-cell RNA sequencing (scRNA-seq), Ribo-seq, and ATAC-seq, was used to dissect underlying mechanisms. A small-molecule library screen, molecular dynamics simulations, and functional assays were used to identify compounds targeting AARS1. AARS1 depletion suppressed tumor progression, remodeled the TME, decreased myeloid-derived suppressor cells and tumor-associated macrophages, and increased cytotoxic T-lymphocyte (CTL) infiltration. Mechanistically, AARS1 interacted with NAT10 to regulate ribosomal loading of Irf7 mRNA, thereby attenuating type I interferon (IFN-I) signaling. Screening identified deleobuvir as a potent AARS1-binding molecule that disrupted the AARS1–NAT10–mRNA complex, restored IFN-I signaling, and enhanced antitumor immunity. Targeting AARS1 in ovarian cancer promotes CTL infiltration and sensitizes tumors to antitumor immunity.

Source: Cell Death and Disease

DOI: 10.1038/s41419-026-09323-7