SERPINE1 Drives Immune Suppression in Pancreatic Cancer via Stromal Fibroblasts

Pancreatic ductal adenocarcinoma (PDAC) is one of oncology's most intractable challenges, marked by late diagnosis, rapid metastasis, and near-universal therapy resistance. Chronic inflammation is a well-established precursor, yet the molecular bridges linking inflammatory signaling to immune evasion and stromal remodeling remain poorly defined. This study set out to fill that gap using an integrative multi-omics framework.

The investigators assembled transcriptomic and clinical data from 123 PDAC patients in TCGA, supplemented by three external cohorts (GSE71989, E-EMBL-6, E-MEXP-1121) spanning normal pancreas, chronic pancreatitis, and PDAC. Differential expression analysis with the limma R package, protein–protein interaction modeling via CytoHubba, and functional enrichment through GO/KEGG and GSEA converged on 11 hub genes, with SERPINE1 emerging as the most consistent central node. Its prognostic relevance was confirmed by survival analyses, and immunotherapy response was assessed using the IMvigor210 cohort and the TIDE algorithm.

SERPINE1, encoding plasminogen activator inhibitor-1 (PAI-1), was robustly upregulated in PDAC versus normal and chronic pancreatitis tissue across all cohorts. Elevated SERPINE1 expression was tightly associated with a profoundly immunosuppressive tumor microenvironment—including reduced cytotoxic T-cell infiltration and elevated immunosuppressive stromal signatures—and predicted diminished responsiveness to immune checkpoint blockade. Structure-based molecular docking identified the multikinase inhibitor Lenvatinib and the Src/BCR-ABL inhibitor Dasatinib as previously unrecognized candidate SERPINE1 inhibitors, opening a drug-repurposing avenue.

Single-cell RNA sequencing of six PDAC patients (GSE212966, processed with Seurat, SCTransform normalization, and Harmony batch correction) resolved nine major cellular compartments. Critically, fibroblasts—specifically cancer-associated fibroblast (CAF) subpopulations—were identified as the dominant stromal source of SERPINE1, positioning CAFs as orchestrators of SERPINE1-driven crosstalk between inflammation, extracellular matrix remodeling, and immune exclusion. This CAF-centric origin had not been systematically defined in prior PDAC studies.

Functional validation via CRISPR-mediated SERPINE1 knockout in PDAC cell lines significantly impaired proliferation and migration while inducing robust apoptosis, confirming that SERPINE1 is not merely a biomarker but an active driver of tumor aggressiveness. Collectively, these findings establish SERPINE1 as a mechanistically grounded and clinically actionable therapeutic target at the tumor–stroma interface in pancreatic cancer.