Publications
28 October 2026
Targeting alanyl-tRNA synthetase 1 unlocks antitumor immunity by inducing type I interferon signaling in ovarian cancer
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.