Hypoxia in the glioblastoma tumor microenvironment (TME) is a major obstacle to effective treatment. Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis, characterized by high proliferation, infiltration, and resistance to treatment. GBM tumors exhibit tissue hypoxia, which promotes tumor aggressiveness, maintains glioma stem cells, and creates an immunosuppressive TME. Hypoxia overlaps with inflammatory responses, favoring the proliferation of immunosuppressive cells and inhibiting cytotoxic T cell development. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, are promising but face challenges such as tumor heterogeneity, immunosuppressive TME, and BBB restrictiveness. Strategies to address these challenges, including combination therapies and targeting hypoxia, are being explored to improve GBM outcomes. Targeting hypoxia in combination with immunotherapy may enhance treatment efficacy. GBM tumors are highly heterogeneous, with genetic, cellular, and spatial diversity. This heterogeneity contributes to the complexity of GBM biology and challenges the development of targeted therapies. The TME is immunosuppressive, with regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and other immunosuppressive cells inhibiting anti-tumor immune responses. VEGF and other factors contribute to immunosuppression by reducing T-effector cell infiltration and activating Tregs. GBM tumors also exploit immune checkpoint molecules to dampen anti-tumor immunity. Myeloid cells in the TME play a key role in immunosuppression, promoting Treg survival and function. The BBB restricts immune cell entry into the tumor, limiting the effectiveness of immunotherapy. Aberrant neo-angiogenesis in GBMs leads to the formation of leaky, abnormal blood vessels, contributing to hypoxia and tumor progression. Hypoxia in GBMs activates the STAT3 pathway, promoting immunosuppression and tumor growth. Hypoxia also recruits immunosuppressive cells such as tumor-associated macrophages and Tregs, further suppressing immune responses. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, are being explored as novel treatments for GBM. Vaccines targeting tumor-specific antigens have shown some efficacy, but challenges remain in translating results to clinical practice. Immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4, have shown promise in some cancers but have limited efficacy in GBM due to the immunosuppressive TME. CAR-T cell therapy has shown success in blood cancers but has limited efficacy in GBM due to the harsh TME and immune suppression. Tumor Treating Fields (TTFields) therapy is a non-invasive treatment that disrupts glioblastoma cell division and has shown promise in improving survival in GBM patients. ImmunomodulatoryHypoxia in the glioblastoma tumor microenvironment (TME) is a major obstacle to effective treatment. Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis, characterized by high proliferation, infiltration, and resistance to treatment. GBM tumors exhibit tissue hypoxia, which promotes tumor aggressiveness, maintains glioma stem cells, and creates an immunosuppressive TME. Hypoxia overlaps with inflammatory responses, favoring the proliferation of immunosuppressive cells and inhibiting cytotoxic T cell development. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, are promising but face challenges such as tumor heterogeneity, immunosuppressive TME, and BBB restrictiveness. Strategies to address these challenges, including combination therapies and targeting hypoxia, are being explored to improve GBM outcomes. Targeting hypoxia in combination with immunotherapy may enhance treatment efficacy. GBM tumors are highly heterogeneous, with genetic, cellular, and spatial diversity. This heterogeneity contributes to the complexity of GBM biology and challenges the development of targeted therapies. The TME is immunosuppressive, with regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and other immunosuppressive cells inhibiting anti-tumor immune responses. VEGF and other factors contribute to immunosuppression by reducing T-effector cell infiltration and activating Tregs. GBM tumors also exploit immune checkpoint molecules to dampen anti-tumor immunity. Myeloid cells in the TME play a key role in immunosuppression, promoting Treg survival and function. The BBB restricts immune cell entry into the tumor, limiting the effectiveness of immunotherapy. Aberrant neo-angiogenesis in GBMs leads to the formation of leaky, abnormal blood vessels, contributing to hypoxia and tumor progression. Hypoxia in GBMs activates the STAT3 pathway, promoting immunosuppression and tumor growth. Hypoxia also recruits immunosuppressive cells such as tumor-associated macrophages and Tregs, further suppressing immune responses. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, are being explored as novel treatments for GBM. Vaccines targeting tumor-specific antigens have shown some efficacy, but challenges remain in translating results to clinical practice. Immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4, have shown promise in some cancers but have limited efficacy in GBM due to the immunosuppressive TME. CAR-T cell therapy has shown success in blood cancers but has limited efficacy in GBM due to the harsh TME and immune suppression. Tumor Treating Fields (TTFields) therapy is a non-invasive treatment that disrupts glioblastoma cell division and has shown promise in improving survival in GBM patients. Immunomodulatory