Cuproptosis is implicated in regulating tricarboxylic acid cycle and associated with tumor therapeutic sensitivity, patient outcomes and tumorigenesis. However, the classification and prognostic effect of cuproptosis-associated genes (CAGs), the relationship between cuproptosis and tumor microenvironment (TME) as well as the treatment of lower-grade glioma (LrGG) remain enigmatic.The genetic and transcriptional alterations, prognostic value and classification related to cuproptosis were systematically analyzed. Subtypes of cuproptosis and cuproptosis score (Cuscore) were constructed and further confirmed by two external cohorts. The relationship between cuproptosis and TME, prognosis, and treatment response were also evaluated.Four clusters were identified based on cuproptosis-associated genes. The association between cuproptosis-associated clusters and clinical features, prognosis, immune cell infiltration, and chemotherapy sensitivity were observed. The Cuscore was an independent prognostic indicator in LrGG patients. The nomogram is constructed according to Cuscore and clinical characteristics, and has good predictive ability and calibration. Patients with high Cuscore had a worse prognosis and advanced performance. A higher Cuscore also indicated a higher stromal score, abundant immune infiltration, and increased tumor mutation burden (TMB). High Cuscore was remarkably related to immune checkpoint inhibitors, immunotherapy response and immune phenotype.This study demonstrates the clinical effect of CAGs, and suggests that cuproptosis could be a potential therapeutic target in LrGG.This article is protected by copyright. All rights reserved.