A reproducible epithelial transcriptional state combines interferon-associated and secretory programs in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) exhibits extensive epithelial plasticity, yet epithelial states associated with interferon signaling remain incompletely defined. We analyzed cleaned epithelial cells classified as singlets in two independent PDAC single-cell RNA-sequencing cohorts, GSE155698 and GSE212966, and constructed a composite score combining an interferon-associated module (IFNcore) with an epithelial-secretory module (Secretorycore). VM-high cells consistently co-expressed representative genes from both programs. Within individual PDAC tumors, IFNcore and Secretorycore were positively associated in 14 of 17 GSE155698 samples and 5 of 6 GSE212966 samples. Sample-level effect sizes and leave-one-gene-out analyses further identified IRF1, STAT1, and ELF3 as candidate factors associated with distinct components of the state. The principal findings were preserved after doublet filtering and remained detectable in Harmony- and CopyKAT-based robustness analyses. In the independent GSE62452 cohort, the composite score correlated with a non-overlapping interferon signature among 69 PDAC tumors (Spearman rho = 0.584, P = 1.42 × 10^-7). In TCGA-PAAD, a higher continuous score was associated with poorer overall survival in univariate Cox analysis, although the association was attenuated after adjustment for age, sex, stage, and grade. These findings define a reproducible PDAC epithelial transcriptional state in which interferon-associated activity coexists with secretory epithelial identity and nominate IRF1, STAT1, and ELF3 for subsequent functional investigation.