Stimulator of interferon genes signaling network‑driven prognostic signature for pancreatic cancer: Hub gene discovery with multimodal validation

The stimulator of interferon genes (STING) signaling pathway plays an important role in tumor progression, particularly in immune regulation. However, the functions of STING-related genes in immunologically 'cold' tumors, such as pancreatic ductal adenocarcinoma (PAAD), are yet to be elucidated. The present study aims to investigate the involvement of STING signaling pathway-associated genes in PAAD progression and immune infiltration. Bioinformatics analysis of PAAD transcriptomic data from public cohorts (TCGA and GEO) revealed that the majority of STING-related genes were highly expressed in PAAD. Based on the expression levels of these genes, patients with PAAD from these cohorts were stratified into high-risk and low-risk groups. These STING-related genes exerted differential impacts on tumor mutational burden, immune infiltration and response to immunotherapy. Utilizing these genes, a prognostic model was constructed (hazard ratio, 2.639; P<0.001) and externally validated. Model analysis indicated that interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) and zinc finger DHHC-type containing 1 (ZDHHC1) may possess notable biological functions in PAAD. Subsequent functional experiments involving knockout of IFIT2 and overexpression of ZDHHC1in PAAD cell lines demonstrated that these genes significantly regulated cell proliferation (assessed by CCK-8 assay) and apoptosis (assessed by TUNEL assay) (P<0.001). In summary, the STING signaling pathway is critically involved in PAAD pathogenesis, and the representative genes IFIT2 and ZDHHC1 exhibit distinct functional roles within this context.