Deciphering the single-cell molecular landscape of ampullary cancer: A rare gastrointestinal malignancy.

Ampullary carcinoma (AC) is a rare epithelial cancer, representing around 0.2% of all gastrointestinal malignancies worldwide, with an estimated incidence of 0.73 per 100,000 people. The rarity of AC, combined with the intricate anatomy of its site of origin, often complicates histopathological diagnosis. Recent advances in molecular research, however, have begun to illuminate its underlying biological complexity. In this study, we present the first comprehensive single-cell transcriptomic atlas of AC, encompassing both malignant epithelial populations and the tumor immune microenvironment (TIME). We identified upregulation of oncogenic drivers previously linked to AC, along with an AC-specific transcriptional program featuring potential biomarkers for minimally invasive diagnostics. Furthermore, we characterized an immunosuppressive TIME, enriched in anti-inflammatory-like tumor-associated macrophages (TAMs) and T cell subsets with limited antitumor activity. Collectively, these findings provide a foundational resource for the identification and validation of candidate biomarkers for early detection and targeted therapies in AC.