A novel defined cuproptosis-related signature for predicting prognosis and immunotherapy efficacy in pancreatic cancer

Abstract

Abstract Background Cuproptosis, a newly discovered copper-dependent programmed cell death, was separate from existing other forms of cell death. Nevertheless, the characteristics of the cuproptosis-based molecular signature and the intertumoral heterogeneity of cell death in pancreatic cancer (PC) remains less studied. Materials and Methods To explore the intertumoral heterogeneity of cell death in PC patients, we assessed the enrichment scores of five reported cell death modes by single sample gene set enrichment (ssGSEA) analysis. Then, multiple bioinformatics and in vitro validation were generated to systematically assess expression profile, prognosis, and immune cell infiltration of cuproptosis-related genes (CGs) in PC. Results Our study found cuproptosis exhibited the only protective effect on survival compared to other cell death mode. We also evaluated the alterations in genomic backgrounds of CGs. We next identified two distinct molecular subtypes and determined the latent roles of CGs in tumor microenvironment (TME), clinical features and immunotherapy response. Accordingly, we observed that CGs subtype was associated with poor survival, stromal activation, immunosuppression and immunotherapy resistance in PC patients. Moreover, we established a highly accurate nomogram to facilitate the clinical viability of CGs score. A high CGs score, characterized by elevated mutation burden, and stromal activation, proved a poor prognosis. Additionally, higher of anti-PD-1 resistant-related signature was observed in high CGs score group. Conclusion These findings define a novel prognostic CGs signature for predicting clinical outcomes and immunotherapy response in PC, which contribute to precise risk stratifications and enable the exploration of more potent immunotherapy strategies.