MUC5AC-driven transcriptional reprogramming for stratification of pancreatic ductal adenocarcinoma by immune suppression and stromal remodeling.

4194 Background: Mucin 5AC (MUC5AC) is aberrantly expressed in pancreatic ductal adenocarcinoma (PDAC) and associated with tumor progression; however, its role in altering the tumor immune microenvironment (TIME) and immunotherapy-relevant pathways is poorly understood. Thus, we evaluated whether MUC5AC expression delineates PDAC into distinct transcriptional and immunologic subtypes based on TIME. Methods: Bulk RNA-seq data from 730 PDAC tumors (Oncology Research Information Exchange Network, ORIEN) and 360 normal pancreatic tissues (GTEx) were analyzed. Differential gene expression and pathway enrichment were assessed using Gene Ontology and KEGG analyses. Immune infiltration and stromal states were inferred using multiple complementary deconvolution algorithms (CIBERSORT and xCell). Tumors in the lowest quartile of MUC5AC expression (≤25th percentile; MUC5AC-low, MUC5AC-L) were compared with the remaining samples (MUC5AC-high, MUC5AC-H). Associations between MUC5AC expression and immune cell populations and immunomodulatory genes were evaluated by using correlations and group-based analyses with false discovery rate (FDR) corrections. Results: Principal component analysis demonstrated clear separation between PDAC tumors and normal pancreas and revealed distinct transcriptional programs between MUC5AC-H (N = 544) and MUC5AC-L (N = 186) tumors. MUC5AC-H tumors exhibited a profoundly immunosuppressive and stromal-remodeled TIME, including enrichment of M2 macrophages, regulatory T cells, activated natural killer ells, fibroblast-associated signatures, and significantly higher immune and stromal scores (multiple FDR ≤10⁻⁶ to ≤10⁻²⁸). In contrast, MUC5AC-L tumors showed relatively enrichment of immune-activating populations, including naïve B cells, dendritic cell subsets, resting CD4⁺ memory T cells, and CD8⁺ T cells (multiple FDR < 10⁻¹⁵). MUC5AC expression strongly correlated with immune checkpoint genes CD274 (PD-L1) and TIGIT , and with multiple suppressive immune populations (p < 0.01 to < 10⁻¹⁰). Conclusions: MUC5AC defines a transcriptionally distinct, immunosuppressive PDAC subtype characterized by stromal activation, macrophage/Treg enrichment, and immune checkpoint engagement. MUC5AC may serve as a biomarker for immune stratification and supports rational combination strategies integrating stromal targeting with immune checkpoint modulation in PDAC.