BackgroundCopper homeostasis is associated with malignant biological behavior in various tumors. The excessive accumulation of copper can induce tumor death, which is named cuproptosis, and it is also closely related to tumor progression and the formation of the immune microenvironment. However, the associations of cuproptosis with glioblastoma (GBM) prognosis and microenvironment construction are poorly understood.MethodFirst, TCGA and GEO (GSE83300, GSE74187) merged datasets were used to analyze the association of cuproptosis-related genes (CRGs) with GBM. Then, we performed cluster analysis of CRGs in GBM from the GEO (GSE83300, GSE74187) and TCGA merged datasets. Subsequently, the prognostic risk model was constructed by least absolute shrinkage and selection operator (LASSO) according to gene expression features in CRG clusters. Next, we performed a series of in-depth analyses, including tumor mutational burden (TMB) analysis, cluster analysis, and GBM IDH status prediction. Finally, RARRES2 was identified as a target gene for GBM treatment, especially IDH wild-type GBM. In addition, we further analyzed the correlation of CRG clusters and RARRES2 expression with the GBM immune microenvironment by ESTIMATE and CIBERSORT analyses. In vitro experiments were conducted to demonstrate that targeting RARRES2 inhibits glioblastoma progression and macrophage infiltration, particularly IDH wild-type GBM.ResultsIn the present study, we demonstrated that the CRG cluster was closely related to GBM prognosis and immune cell infiltration. Moreover, the prognostic risk model constructed with the three genes (MMP19, G0S2, RARRES2) associated with the CRG clusters could well evaluate the prognosis and immune cell infiltration in GBM. Subsequently, after further analyzing the tumor mutational burden (TMB) in GBM, we confirmed that RARRES2 in the prognostic risk model could be used as a crucial gene signature to predict the prognosis, immune cell infiltration and IDH status of GBM patients.ConclusionThis study fully revealed the potential clinical impact of CRGs on GBM prognosis and the microenvironment, and determined the effect of the crucial gene (RARRES2) on the prognosis and tumor microenvironment construction of GBM, meanwhile, our study also revealed over-expressed RARRES2 is related to the IDH satus of GBM, which provides a novel strategy for the treatment of GBM, particularly IDH wild-type GBM.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12935-023-02950-6.