Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, characterized by high proliferation, infiltrative growth, and resistance to traditional treatments. Despite maximum treatment, GBM patients have a dismal prognosis. Tissue hypoxia in GBM tumors promotes tumor aggressiveness, maintains glioma stem cells, and creates an immunosuppressive microenvironment. This article reviews how hypoxic conditions overlap 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, show promise but are hindered by tumor heterogeneity, immunosuppressive TME, and BBB restrictiveness. Strategies to address these challenges, such as combination therapies and targeting hypoxia, are actively being explored to improve outcomes for GBM patients. Targeting hypoxia in combination with immunotherapy represents a potential strategy to enhance treatment efficacy.Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, characterized by high proliferation, infiltrative growth, and resistance to traditional treatments. Despite maximum treatment, GBM patients have a dismal prognosis. Tissue hypoxia in GBM tumors promotes tumor aggressiveness, maintains glioma stem cells, and creates an immunosuppressive microenvironment. This article reviews how hypoxic conditions overlap 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, show promise but are hindered by tumor heterogeneity, immunosuppressive TME, and BBB restrictiveness. Strategies to address these challenges, such as combination therapies and targeting hypoxia, are actively being explored to improve outcomes for GBM patients. Targeting hypoxia in combination with immunotherapy represents a potential strategy to enhance treatment efficacy.