Why Do Glioblastoma Treatments Fail?

Glioblastoma (GBM) is the most aggressive brain tumor, characterized by high recurrence rates and poor patient outcomes. Treatment failure is driven by multiple factors, including complex tumor heterogeneity, the presence of cancer stem cells, the immunosuppressive tumor microenvironment (TME), and many others. GBM’s heterogeneity underlines its ability to resist therapies and adapt to the TME. The TME, which is highly immunosuppressive and shaped by hypoxia, impairs anti-tumor immunity and limits the efficacy of immunotherapy. The blood–brain barrier (BBB) remains a major obstacle to delivering sufficient drug concentrations to the tumor by restricting the penetration of therapeutic agents. Another problem is the lack of reliable biomarkers to perform better patient stratification or even guide personalized treatments, resulting in generalized therapeutic approaches that do not adequately address GBM complexities. This review highlights the multifactorial nature of GBM treatment failure and highlights the need for a paradigm shift and innovative, personalized strategies. A deeper understanding of tumor biology and advances in translational research will be crucial to developing effective therapies and improving patient outcomes in this devastating disease.