The Complexity of Malignant Glioma Treatment

Simple Summary: This review describes the dynamic influence of the tumor microenvi-ronment during treatment of malignant glioma. The mechanism behind five hallmarksare outlined: glioma stem-like cells in particular (GSCs), vascularization and hypoxia,metabolic reprogramming, tumor-promoting inflammation and sustained proliferativesignaling. A multimodal immunotherapy treatment plan is proposed, explaining how eachhallmark can be targeted over time. Repeated tumor monitoring is deemed vital to alterthe treatment plan when needed.Abstract: Malignant glioma is a highly aggressive, therapeutically non-responsive, anddeadly disease with a unique tumor microenvironment (TME). Of the 14 currently recog-nized and described cancer hallmarks, five are especially implicated in malignant gliomaand targetable with repurposed drugs: cancer stem-like cells, in general, and glioma stem-like cells in particular (GSCs), vascularization and hypoxia, metabolic reprogramming,tumor-promoting inflammation and sustained proliferative signaling. Each hallmark drivesmalignant glioma development, both individually and through interactions with other hall-marks, in which the TME plays a critical role. To combat the aggressive malignant gliomaspatio-temporal heterogeneity driven by TME interactions, and to overcome its therapeuticchallenges, a combined treatment strategy including anticancer therapies, repurposeddrugs and multimodal immunotherapy should be the aim for future treatment approaches