Glioblastoma (GBM) is a highly malignant brain cancer with a poor prognosis despite standard treatments. This investigation aimed to explore the feasibility of PTPN6 to combat GBM with immunotherapy. Our study employed a comprehensive analysis of publicly available datasets and functional experiments to assess PTPN6 gene expression, prognostic value, and related immune characteristics in glioma. We evaluated the influence of PTPN6 expression on CD8+ T cell exhaustion, immune suppression, and tumor growth in human GBM samples and mouse models. Our findings demonstrated that PTPN6 overexpression played an oncogenic role in GBM and was associated with advanced tumor grades and unfavorable clinical outcomes. In human GBM samples, PTPN6 upregulation showed a strong association with immunosuppressive formation and CD8+ T cell dysfunction, whereas, in mice, it hindered CD8+ T cell infiltration. Moreover, PTPN6 facilitated cell cycle progression, inhibited apoptosis, and promoted glioma cell proliferation, tumor growth, and colony formation in mice. The outcomes of our study indicate that PTPN6 is a promising immunotherapeutic target for the treatment of GBM. Inhibition of PTPN6 could enhance CD8+ T cell infiltration and improve antitumor immune response, thus leading to better clinical outcomes for GBM patients.