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Background: Chronic inflammation is increasingly recognized as a fundamental driver of pancreatic ductal adenocarcinoma (PDAC) initiation and progression. Although numerous bioinformatics studies have characterized genetic alterations in PDAC, the key inflammatory regulators that bridge tumor cells and the immunosuppressive stroma remain unclear. Methods: functional assays were employed to validate gene expression patterns and mechanistic functions within the PDAC microenvironment. Results: expression was tightly linked to a profoundly immunosuppressive tumor microenvironment and predicted diminished responsiveness to immunotherapy across datasets. Structure-based molecular docking further identified Lenvatinib and Dasatinib as previously unappreciated candidate inhibitors of SERPINE1, suggesting actionable therapeutic opportunities. Single-cell transcriptomic profiling resolved nine major cellular compartments and pinpointed fibroblasts as the principal stromal niche orchestrating SERPINE1-driven crosstalk between inflammation and immune evasion, a cellular origin that has not been systematically defined before. Translational analyses demonstrated consistently elevated SERPINE1 in tumor tissues, and functional validation using CRISPR-mediated knockout in PDAC cell lines significantly impaired proliferation and migration while inducing robust apoptosis, thereby establishing SERPINE1 as a previously underappreciated but essential driver of PDAC aggressiveness. Conclusions: This integrative multi-omics and single-cell analysis establishes SERPINE1 as a central orchestrator of inflammation-driven stromal remodeling and immune evasion in PDAC. Its strong prognostic power, combined with newly revealed druggability, positions SERPINE1 as a tractable therapeutic axis for precision immunotherapy and rational drug repurposing. These findings provide a mechanistically grounded and clinically actionable entry point into targeting the inflammatory tumor microenvironment of pancreatic cancer.
Wang et al. (Mon,) studied this question.