PPY‐Induced iCAFs Cultivate an Immunosuppressive Microenvironment in Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by cancer cells surrounded by affluent stromal components, which may underlie their limited response to various therapeutic interventions, including immunotherapy. Inflammatory cancer‐associated fibroblasts (iCAFs), a crucial subset of CAFs within the PDAC microenvironment, play a pivotal role in shaping an immunosuppressive microenvironment. In this study, single‐cell RNA sequencing analysis is performed to screen for cancer cells‐secreted proteins associated with iCAF induction, and PPY (pancreatic polypeptide) is validated as a potent inducer. Unlike previously reported iCAF inducers, PPY is a gastrointestinal hormone predominantly expressed in the pancreas, suggesting that targeting it may have minimal systemic effects. Multiplex immunohistochemistry (mIHC) on human PDAC tissue microarrays, orthotopic allograft mouse models, and co‐culture experiments are utilized to validate the crucial role of PPY in iCAF induction. Mechanistic studies integrating mRNA sequencing, immunoprecipitation‐mass spectrometry, and molecular docking reveal that PPY induces iCAFs by activating the non‐canonical NF‐κB pathway through EGFR. Importantly, targeting PPY enhanced the efficacy of anti‐PD‐1 immunotherapy in KPC ( Kras LSL‐G12D/+ ; Trp53 LSL‐R172H/+ ; Pdx1 ‐Cre) mice, as evidenced by reduced tumor burden on PET‐CT imaging and improved survival. This research is expected to provide a novel strategy for improving immunotherapy in PDAC by targeting a key inducer of iCAFs.