Immunotherapeutic strategies for glioblastoma (GBM) face significant challenges due to the tumor's unique characteristics, including its anatomical location protected by the blood-brain barrier (BBB), high invasiveness, tumor heterogeneity, and an immunosuppressive tumor microenvironment (TME). Despite advances in immunotherapy, current treatments have not met expectations for GBM, with limited clinical success. GBM remains uniformly fatal, with a median survival of less than 2 years. The review highlights the intrinsic features of GBM that hinder both conventional and immunotherapeutic approaches. It also analyzes current immune-based therapies under clinical evaluation, including immune checkpoint inhibitors, adoptive T cell therapies, vaccination strategies, and virus-based approaches. The review emphasizes the need for innovative strategies to overcome the immunosuppressive TME and improve patient outcomes. Key challenges include BBB penetration, tumor heterogeneity, and the immunosuppressive TME, which limit the effectiveness of immunotherapies. Despite these challenges, emerging strategies such as combination therapies, novel vaccines, and oncolytic virotherapy show promise. The review underscores the importance of understanding GBM's unique biology to develop more effective immunotherapies. Current clinical trials are exploring various approaches, including DNA/RNA vaccines, peptide vaccines, and dendritic cell vaccines, to enhance immune responses against GBM. While results are promising, further research is needed to translate these findings into effective treatments for GBM patients.Immunotherapeutic strategies for glioblastoma (GBM) face significant challenges due to the tumor's unique characteristics, including its anatomical location protected by the blood-brain barrier (BBB), high invasiveness, tumor heterogeneity, and an immunosuppressive tumor microenvironment (TME). Despite advances in immunotherapy, current treatments have not met expectations for GBM, with limited clinical success. GBM remains uniformly fatal, with a median survival of less than 2 years. The review highlights the intrinsic features of GBM that hinder both conventional and immunotherapeutic approaches. It also analyzes current immune-based therapies under clinical evaluation, including immune checkpoint inhibitors, adoptive T cell therapies, vaccination strategies, and virus-based approaches. The review emphasizes the need for innovative strategies to overcome the immunosuppressive TME and improve patient outcomes. Key challenges include BBB penetration, tumor heterogeneity, and the immunosuppressive TME, which limit the effectiveness of immunotherapies. Despite these challenges, emerging strategies such as combination therapies, novel vaccines, and oncolytic virotherapy show promise. The review underscores the importance of understanding GBM's unique biology to develop more effective immunotherapies. Current clinical trials are exploring various approaches, including DNA/RNA vaccines, peptide vaccines, and dendritic cell vaccines, to enhance immune responses against GBM. While results are promising, further research is needed to translate these findings into effective treatments for GBM patients.