Identification of cuproptosis-related patterns and construction of a scoring system for predicting prognosis, tumor microenvironment-infiltration characteristics, and immunotherapy efficacy in breast cancer

Background: Cuproptosis, a recently discovered refreshing form of cell death, is distinct from other known mechanisms. As copper participates in cell death, the induction of cancer cell death with copper ionophores may emerge as a new avenue for cancer treatment. However, the role of cuproptosis in tumor microenvironment (TME) cell infiltration remains unknown. Methods: We systematically evaluated the cuproptosis patterns in The Cancer Genome Atlas (TCGA) database in breast cancer (BRCA) samples based on 10 cuproptosis-related genes (CRGs), and correlated these patterns with the prognosis and characteristics of TME cell infiltration. A principal component analysis algorithm was used to construct a cuproptosis score to quantify the cuproptosis pattern in individual tumors. Further, the relationships between the cuproptosis score and transcription background, clinical features, characteristics of TME cell infiltration, drug response, and efficacy of immunotherapy were assessed. Results: Two distinct cuproptosis patterns with distinct prognoses were identified; their TME characteristics were found to be consistent with the immune-excluded and immune-inflamed phenotypes, respectively. The cuproptosis patterns in individual patients were evaluated using the cuproptosis score based on the cuproptosis phenotype-related genes, contributing to distinguishing biological processes, clinical outcome, immune cell infiltration, genetic variation, and drug response. Univariate and multivariate Cox regression analyses verified this score as an independent prognostic predictor in BRCA. A high cuproptosis score, characterized by immune activation, suggests an inflamed tumor and immune-inflamed phenotype with poor survival and a low cuproptosis score, characterized by immune suppression, indicates a non-inflamed tumor and immune-excluded phenotype with better survival. Significant differences were observed in the IC50 between the high and low cuproptosis score groups receiving chemotherapy and targeted therapy drugs. In the two immunotherapy cohorts, patients with a higher cuproptosis score experienced considerable therapeutic advantages and clinical benefits. Conclusions: This study is the first to elucidate the prominent role of cuproptosis in the clinical outcome and the formation of TME diversity and complexity in BRCA. Estimating cuproptosis patterns in tumors could help predict the prognosis and characteristics of TME cell infiltration and guide more effective chemotherapeutic and immunotherapeutic strategies.