Single-cell Transcriptomic Profiling of Pancreatic Ductal Adenocarcinoma: Epithelial Reprogramming and Systemic Immune Exhaustion

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies, with a five-year survival rate below 10%, underscoring the urgent need to unravel its complex pathophysiology. In this study, we employ an integrative single-cell RNA sequencing (scRNA-seq) approach to comprehensively characterize both the pancreatic tumor microenvironment and peripheral blood mononuclear cells (PBMCs) from PDAC patients and healthy controls. Using Harmony for batch correction and Azimuth for automated cell-type annotation, we identify cell-type-specific transcriptional alterations through differential expression and functional enrichment analyses. Our results reveal a system-wide disruption involving both epithelial and immune compartments. Epithelial cells exhibit a "de-skilling" phenotype, losing digestive enzyme expression while activating metabolic and ribosomal programs that sustain malignant proliferation. The local immune microenvironment displays chronic inflammation and remodeling, whereas systemic immune exhaustion is evident in cytotoxic T, NK, and myeloid populations, marked by impaired effector activity and metabolic imbalance. Collectively, these findings depict PDAC as a coordinated multi-compartmental failure encompassing epithelial reprogramming, local immune dysregulation, and systemic immune collapse, providing a holistic single-cell view of PDAC pathogenesis and offering mechanistic insights that may guide biomarker discovery and the development of targeted therapeutic strategies.