Glioblastoma (GBM) is a highly aggressive brain tumor with limited responsiveness to conventional treatments, leading to a median overall survival of less than 2 years. Despite recent advances in immunotherapy, current approaches have not met expectations in treating GBM. This review systematically addresses the intrinsic features of GBM that hinder both standard therapies and immunotherapies. It also comprehensively analyzes immune-based approaches currently undergoing clinical evaluation for GBM treatment, including immune checkpoint inhibitors, adoptive T cell therapies, vaccination strategies (RNA-, DNA-, and peptide-based vaccines), and virus-based therapies. The review highlights the challenges in delivering treatments due to the anatomical location of the brain, the blood-brain barrier, tumor heterogeneity, and the immunosuppressive nature of the tumor microenvironment. It discusses the potential of combining various immunotherapies and explores novel innovative strategies and future prospects in the field of immunotherapy for GBM.Glioblastoma (GBM) is a highly aggressive brain tumor with limited responsiveness to conventional treatments, leading to a median overall survival of less than 2 years. Despite recent advances in immunotherapy, current approaches have not met expectations in treating GBM. This review systematically addresses the intrinsic features of GBM that hinder both standard therapies and immunotherapies. It also comprehensively analyzes immune-based approaches currently undergoing clinical evaluation for GBM treatment, including immune checkpoint inhibitors, adoptive T cell therapies, vaccination strategies (RNA-, DNA-, and peptide-based vaccines), and virus-based therapies. The review highlights the challenges in delivering treatments due to the anatomical location of the brain, the blood-brain barrier, tumor heterogeneity, and the immunosuppressive nature of the tumor microenvironment. It discusses the potential of combining various immunotherapies and explores novel innovative strategies and future prospects in the field of immunotherapy for GBM.