Pan-cancerN-glycoproteomic atlas of patient-derived xenografts uncovers FAT2 as a therapeutic target for head and neck cancers

SUMMARY Cell surface proteins offer significant cancer therapeutic potential attributable to their accessible membrane localization and central role in cellular signaling. Despite this, their promise remains largely untapped due to the technical challenges inherent to profiling cell surface proteins. Here, we employed N -glycoproteomics to analyze 85 patient-derived xenografts (PDX), constructing Glyco PDXplorer – an in vivo pan-cancer atlas of cancer-derived cell surface proteins. We developed a target discovery pipeline to prioritize proteins with favorable expression profiles for immunotherapeutic targeting and validated FAT2 as a head and neck squamous cancer (HNSC) enriched surface protein with limited expression in normal tissue. Functional studies revealed that FAT2 is essential for HNSC growth and adhesion through regulation of surface architecture and integrin-PI3K signaling. Chimeric antigen receptor (CAR) T cells targeting FAT2 demonstrated potent anti-tumor activity in HNSC models. This work lays the foundation for developing FAT2-targeted therapies and represents a pivotal resource to inform therapeutic target discovery for multiple cancers. HIGHLIGHTS Pan-cancer landscape of cancer-derived cell surface proteins detected in vivo Development of a multi-omic discovery pipeline to prioritize proteins with optimal expression profiles as immunotherapy targets Identification and validation of FAT2 as a head and neck squamous cancer enriched surface protein with minimal expression in normal tissues FAT2 coordinates cell surface organization, adhesion, growth and survival through the integrin-PI3K-AKT pathway FAT2 CAR T cells demonstrate anti-tumour activity in pre-clinical models