Abstract
BACKGROUND: Pancreatic cancer (PC) is characterized by a profoundly immunosuppressive tumor microenvironment and poor prognosis. Dendritic cells (DCs) are pivotal for antigen presentation and T-cell activation, yet their prognostic and mechanistic roles in PC remain incompletely defined. METHODS: This study performed weighted gene co-expression network analysis (WGCNA) on transcriptomic data from The Cancer Genome Atlas (TCGA) and two Gene Expression Omnibus cohorts (GSE62165, GSE85916) to identify DC-related gene modules. Consensus clustering based on these modules stratified patients into two immune phenotypes. A four-gene DC-related risk score (DCRS) was constructed using LASSO-Cox regression and validated in independent cohorts. Single-cell RNA sequencing data from 25 PC samples (GSE242230) were analyzed through cell clustering analysis, cell-cell communication analysis, and pathway-specific analysis. Functional assays following KCTD14 knockdown in CAPAN-1 and PANC-1 cell lines assessed its impact on proliferation, migration, invasion, and TNF signaling. RESULTS: WGCNA identified 130 overlapping DC-related genes enriched in immune pathways. Two DC-related patient clusters exhibited distinct overall survival (OS) (P < 0.05). The DCRS robustly stratified patients into high- and low-risk groups in both TCGA training and validation sets. DCRS demonstrated good predictive potential for OS and there is a significant difference in OS between the two groups of patients (P < 0.05). Single-cell analysis revealed KCTD14 enrichment in malignant epithelial cells and predicted its interaction with DCs via the TNF-TNFRSF1A axis. In vitro, KCTD14 knockdown significantly reduced PC cell proliferation, colony formation, migration, and invasion, and downregulated TNF-α and TNFRSF1A expression (P < 0.01). CONCLUSION: We identified a novel DC-related gene signature that stratifies PC patients by prognosis and highlights KCTD14 as a novel immunomodulatory oncogene acting through the TNF-TNFR1 axis. Our findings provide a foundation for integrating DCRS into clinical risk assessment and for pursuing KCTD14/TNFR1-targeted therapies to overcome DC-mediated immune suppression in pancreatic cancer.