Surface proteomics reveals arginine metabolism as a vulnerability in high grade serous ovarian cancer

The significant lethality of high-grade serous ovarian cancer is driven by the lack of long-term efficacy of current treatments, underscoring the need for developing additional therapeutics. Cell surface proteins represent attractive therapeutic targets yet remain underexplored in high-grade serous ovarian cancer. Here, we employ cell surface N -glycoproteomics to elucidate the cell surface proteomes of high-grade serous ovarian cancer cells alongside normal epithelial and cancer-associated stromal cells, uncovering new opportunities for therapeutic intervention. Integration of cell surface N -glycoproteomics and functional screening reveals multiple minimally characterized, high-grade serous ovarian cancer enriched surface proteins that are critical for high-grade serous ovarian cancer proliferation – most notably, SLC7A1. Multi-omic and functional characterization indicates that SLC7A1 is necessary for HGSC migration, protein synthesis and mitochondrial functions likely linked to its role as an arginine transporter. Finally, we demonstrate that elevated surface expression of SLC7A1 in high-grade serous ovarian cancer reflects dysregulated arginine metabolism, pointing to a putative therapeutic vulnerability. Our work identifies SLC7A1 and arginine metabolism as a previously unrecognized molecular vulnerability in high-grade serous ovarian cancer and provides a framework to guide future therapeutic development.