A novel defined cuproptosis‑related signature score to predict prognosis and immunotherapy efficacy in pancreatic cancer

Cuproptosis, a novel mode of copper-dependent programmed cell death, represents a distinct mechanism separate from other established forms of cell death. The present study aimed to explore the intertumoral heterogeneity of cell death and its relationship with the tumor microenvironment (TME) in pancreatic cancer (PC). Multiple bioinformatics approaches, using multi-omics data from The Cancer Genome Atlas, Genome Tissue Expression, International Cancer Genome Consortium, Gene Expression Omnibus and Clinical Proteomic Tumor Analysis Consortium datasets, and <i>in vitro</i> validation were employed to comprehensively analyze the expression profile, prognostic value and immune cell infiltration of cuproptosis-related genes (CGs) in PC. The enrichment scores of five reported cell death modes were assessed by single-sample gene set enrichment analysis. The results revealed that cuproptosis exhibited the only protective effect on survival compared with other cell death modes and CDK inhibitor 2A was the core gene involved in PC cuproptosis status. The present study also evaluated the alterations in genomic backgrounds and the expression of CGs, and detected dysregulated mRNA levels, cell-free DNA levels and protein levels of CGs in PC. Subsequently, two distinct cuproptosis subtypes (CG cluster A and CG cluster B) were identified, and the potential roles of CGs in the TME, clinical features and immunotherapy response were delineated. Notably, it was observed that CG cluster B was associated with poor survival, stromal activation, immunosuppression and immunotherapy resistance in patients with PC. Furthermore, a highly accurate nomogram was developed to enhance the clinical applicability of the cuproptosis-associated risk score. A high-risk score, characterized by an increased mutation burden and stromal activation, was associated with worse survival. Furthermore, compared with the low-risk score group, a higher anti-programmed cell death protein-1 resistant-related signature was observed in the high-risk score group. These findings define a novel prognostic cuproptosis-related signature for the prediction of clinical outcomes and immunotherapy response in PC.