Development and validation of a cuproptosis-related lncRNA signature for predicting prognosis and immunotherapy response in breast cancer: a retrospective analysis of TCGA data.

[BACKGROUND] Cuproptosis, a copper-dependent mode of regulated cell death, may expose metabolic liabilities in breast cancer (BRCA). Long non-coding RNAs (lncRNAs) can orchestrate metabolic and immune programs, yet their connection to cuproptosis in BRCA remains unclear. This study aimed to identify cuproptosis-related lncRNAs with prognostic value and to construct a risk model for predicting survival, immune characteristics, and potential therapeutic response in BRCA.

[METHODS] Transcriptomic profiles and clinical data of 1,082 patients with breast cancer were retrieved from The Cancer Genome Atlas (TCGA) database. Cuproptosis-related lncRNAs were identified by co-expression analysis with 17 cuproptosis genes. Patients were randomly divided into training and testing cohorts, and prognostic lncRNAs were screened using univariate Cox regression and least absolute shrinkage and selection operator (LASSO)-Cox regression analyses. Model performance was evaluated using Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, C-index analysis, and nomogram calibration.

[RESULTS] We developed and internally validated a cuproptosis-related five-lncRNA risk score that stratified overall survival (OS) in training and testing cohorts, with time-dependent area under the curve (AUC) of 0.759/0.662/0.625 and 0.666/0.602/0.597 at 1/3/5 years, respectively, and remained independent of age and stage. Immune profiling showed that increasing risk was associated with higher antigen-presenting cell (APC) co-stimulation but lower human leukocyte antigen (HLA) and type I interferon (IFN-I) response, suggesting a potential association with tumor immune microenvironmental remodeling. Consistently, tumor mutational burden (TMB) differed across risk strata and provided complementary prognostic information, while lower tumor immune dysfunction and exclusion (TIDE) scores in the low-risk group suggested a higher likelihood of benefit from immune checkpoint blockade (ICB). Exploratory drug-response inference further indicated distinct therapeutic vulnerabilities between risk groups.

[CONCLUSIONS] A cuproptosis-derived five-lncRNA axis integrates prognosis with immune state, mutation burden, and predicted therapy response, enabling a stratification framework for BRCA.