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The present review explores the latest advancements in targeted therapies for GBM, emphasizing the critical role of the blood\u2010brain barrier (BBB), blood\u2010brain\u2010tumor barrier, tumor microenvironment, and genetic mutations in influencing treatment outcomes. The impact of the key hallmarks of GBM, for example, chemoresistance, hypoxia, and the presence of glioma stem cells on the disease progression and multidrug resistance are discussed in detail. The major focus is on the innovative strategies aimed at overcoming these challenges, such as the use of monoclonal antibodies, small\u2010molecule inhibitors, and novel drug delivery systems designed to enhance drug penetration across the BBB. Additionally, the potential of immunotherapy, specifically immune checkpoint inhibitors and vaccine\u2010based approaches, to improve patient prognosis was explored. 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