Pancreatic polypeptide (PPY) is a gastrointestinal hormone predominantly expressed in the pancreas that functions as a regulator of pancreatic and gastrointestinal physiology 1. PPY acts as a neuropeptide hormone through G protein-coupled receptor signaling pathways, with documented roles in appetite regulation alongside glucagon-like peptide 1 2. Beyond its canonical endocrine functions, PPY has emerged as a potent inducer of inflammatory cancer-associated fibroblasts (iCAFs) in pancreatic ductal adenocarcinoma (PDAC), shaping an immunosuppressive microenvironment 1. Mechanistically, PPY activates the non-canonical NF-κB pathway through EGFR signaling to promote iCAF differentiation 1. Clinically, PPY-cell hyperplasia (PPY-H) can accompany pancreatic neuroendocrine neoplasias, with evidence suggesting PPY-H may be responsible for gastrointestinal symptoms including epigastric pain and cholestasis 3. In pancreatic islet biology, PPY-producing PP-cells are relatively rare, with bihormonal cells containing PPY being exceedingly uncommon and not representing unique lineages 4. Therapeutically, targeting PPY enhances anti-PD-1 immunotherapy efficacy in PDAC, reducing tumor burden and improving survival 1, suggesting PPY represents a novel immunotherapeutic target with minimal predicted systemic effects due to its localized pancreatic expression.