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The combination of therapeutic resistance and high mortality makes it both a challenging target and a devastating diagnosis. Of these, one in two is characterized as glioblastoma (GBM) with a median survival rate of only 13.5\u2009months with the current standard of therapy. Modern interventions, such as PD\u20101 and CTLA\u20104 checkpoint inhibition and autologous CAR T cell delivery, remain stymied by both the difficult nature of drug delivery to the brain and the inherent immunosuppressive tumor microenvironment. However, recent advances in the characterization of GBM have unveiled promising new therapeutic avenues aiming to target and eliminate the tumor. In this review, we summarize the mechanisms through which GBM is initiated, localized, and eludes therapy responses and provide an update on recent advances made within this therapeutic space to overcome GBM\u2010mediated immunosuppression. 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