Proteogenomic characterization of pancreatic neuroendocrine tumors uncovers hypoxia and immune signatures in clinically aggressive subtypes.

Pancreatic neuroendocrine tumors (PanNETs) represent well-differentiated endocrine neoplasms with variable clinical outcomes. Predicting patient outcomes using the current tumor grading system is challenging. In addition, traditional systemic treatment options for PanNETs, such as somatostatin analogs or cytotoxic chemotherapies, are very limited. To address these issues, we characterized PanNETs using integrated proteogenomics and identified four subtypes. Two proteomic subtypes showed high recurrence rates, suggesting clinical aggressiveness that was missed by current classification. Hypoxia and inflammatory pathways were significantly enriched in the clinically aggressive subtypes. Detailed analyses revealed metabolic adaptation via glycolysis upregulation and oxidative phosphorylation downregulation under hypoxic conditions. Inflammatory signature analysis revealed that immunosuppressive molecules were enriched in immune hot tumors and might be immunotherapy targets. In this study, we characterized clinically aggressive proteomic subtypes of well-differentiated PanNETs and identified candidate therapeutic targets.