TREM1-Mediated neutrophil extracellular trap formation promotes pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive tumor microenvironment and dismal prognosis. In this study, we integrated clinical hematological profiles, The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA-PAAD) bulk transcriptomic data, and single-cell RNA sequencing (scRNA-seq) data from human PDAC lesions for bioinformatic screening of core regulatory molecules, followed by in vitro functional assays and clinical sample validation. We identified activated neutrophils as the only myeloid lineage progressively enriched with advancing tumor stage, and delineated four neutrophil subsets among which the tumor-enriched Neu_CCL4L2 and Neu_LST1 populations displayed the strongest NETosis program, with triggering receptor expressed on myeloid cells 1 (TREM1) serving as a candidate upstream regulator. TREM1 expression positively correlated with the neutrophil extracellular traps (NETs) biosynthetic program and predicted poor overall survival; ectopic TREM1 overexpression robustly induced NETosis - an effect attenuated by TREM1 knockdown - and TREM1-activated neutrophils promoted PDAC cell proliferation, migration, and epithelial-mesenchymal transition (EMT) via NETs-dependent paracrine signaling, a finding further corroborated by clinical specimens. Collectively, TREM1 facilitates PDAC progression by promoting NETs formation, and the TREM1–NETs signaling axis represents a promising prognostic biomarker and therapeutic target for PDAC.