Comprehensive Analysis of Cuproptosis-related genes in prognosis, tumor microenvironment infiltration, and Immunotherapy response in gastric cancer

Abstract Cuproptosis is the most recently identified copper-dependent cell death form that influences tricarboxylic acid (TCA) cycle. However, the relationship between cuproptosis and clinical prognosis, tumor microenvironment infiltration (TME), and response to immunotherapy remains unclear. Thus, we performed the following analysis. Single-sample gene-set enrichment analysis (ssGSEA) was employed to construct cuproptosisScore (cpS) and 1378 gastric cancer (GC) patients from five independent public datasets were classified into high- or low-cpS groups according to the median of cpS. Then the impacts of cuproptosis on tumor microenvironment infiltration (TME), biological function, response to immunotherapy, and clinical prognosis of GC were evaluated. RiskScore and nomogram were constructed using Lasso Cox regression algorithm to validate its predictive capability in GC patients. Compared to patients with high cpS, patients with low cpS exhibited poorer prognosis, higher TNM stage, and stronger stromal activation. Meanwhile, the analysis of response to immunotherapy confirmed patients with high cpS could better benefit from immunotherapy and had a better susceptibility to chemotherapeutic drugs. 9 prognosis-related signatures were collected based on differentially expressed genes (DEGs) of cpS groups. Finally, a riskScore model was constructed using the multivariate Cox (multi-Cox) regression coefficients of prognosis-related signatures and had an excellent capability of predicting 1-, 3-, and 5-year survival in GC patients. In summary, this study revealed the role of curproptosis in TME, response to immunotherapy, and clinical prognosis in GC, which highlighted the significant clinical implications of curproptosis and provided novel ideas for the therapeutic application of cuproptosis in GC.