PLXDC1+ Tumor‐Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma

Abstract Pancreatic stellate cells (PSCs) contribute to pancreatic ductal adenocarcinoma (PDAC) progression and therapeutic resistance, yet their detailed functions remain unclear. This study combined RNA sequencing and assay for transposase‐accessible chromatin using sequencing (ATAC‐seq) on sorted PSCs from adjacent normal and PDAC tissues to investigate their transcriptional and epigenetic activation. PSCs heterogeneity and functions are characterized through bulk, single‐cell, and spatial transcriptomes, as well as in situ sequencing. The clinical relevance of PSCs in immunotherapy is assessed using an in‐house immune‐checkpoint blockade (ICB) treatment cohort. Findings showed that stress and hypoxia signaling activated PSCs in PDAC. Three common PSCs (CPSCs) and four tumor‐associated PSCs (TPSCs) are identified, each with distinct functions. CPSCs differentiated into CCL19 + TPSCs in immune‐enriched regions, MYH11 + TPSCs in the stromal region, and PLXDC1 + TPSCs, which exhibited cancer‐associated myofibroblasts (myCAFs) phenotype linked to poor prognosis. Notably, PLXDC1 + TPSCs, located near aggressive LRRC15 + myCAFs and SPP1 + macrophages, formed a desmoplastic and immunosuppressive niche around the tumor boundary, promoting CD8 T cell exhaustion. Single‐cell transcriptomics of PDAC patients treated with ICB revealed that PLXDC1 + TPSCs correlated with poor immunotherapy efficacy. Overall, this study provides key insights into PSCs in PDAC and potential therapeutic targets.