Glioma is the most prevalent malignancy in the central nervous system. The impact of ion-induced cell death on malignant tumors' development and immune microenvironment has attracted broad attention in recent years. Cuproptosis is a novel copper-dependent mechanism that could potentially regulate tumor cell death by targeting mitochondria respiration. However, the role of cuproptosis in gliomas remains unclear. In the present study, we investigated the relationships between the expression of cuproptosis-related genes (CRGs) and tumor characteristics, including prognosis and microenvironment of glioma, by analyzing multiple public databases and our cohort. Consensus clustering based on the expression of twelve CRGs stratified the glioma patients into three subgroups with significantly different prognosis and immune microenvironment landscapes. Reduced immune infiltration was associated with the less aggressive CRG cluster. A prognostic CRGs risk signature (CRGRS), based on eight critical CRGs, classified the patients into low- and high-risk groups in the training set and was endorsed by validation sets from multiple cohorts. The high-risk group manifested a shorter overall survival, and further survival analysis demonstrated that the CRGRS was an independent prognostic factor. The nomogram combining CRGRS and other clinicopathological factors exhibited good accuracy in predicting the prognosis of glioma patients. Moreover, analyses of tumor immune microenvironment indicated that higher CRGRS was correlated with increased immune cell infiltration but diminished immune function. Gliomas in the high-risk group exhibited higher expression of multiple immune checkpoints, including PD-1 and PD-L1, and a better predicted therapy response to immune checkpoint inhibitors. In conclusion, our study elucidated the connections between CRGs expression and the aggressiveness of gliomas, and the application of CRGRS derived a new robust model for prognosis evaluation of glioma patients. The correlations between the profiles of CRGs expression and immune tumor microenvironment illuminated prospects and potential indications of immunotherapy for glioma.Copyright © 2022 Chen, Zhang, Yuan, Wang, Li, Li, Zuo, Feng, Chen and Liu.