Drug resistance in glioblastoma: Challenges, mechanisms and therapeutic strategies (Review).

Glioblastoma multiforme (GBM), the most aggressive and prevalent type of brain cancer, presents a formidable therapeutic challenge due to its high degree of drug resistance. Despite advances in chemotherapy, targeted therapy and immunotherapy, patient outcomes remain dismal, with a 5-year survival rate of only 7%. Resistance mechanisms are multifactorial, including the restrictive nature of the blood-brain barrier (BBB), tumor heterogeneity and adaptive responses within the tumor microenvironment (TME). The BBB limits drug delivery, while efflux transporters further reduce therapeutic efficacy. Additionally, the vast molecular genetic and cellular heterogeneity of a glioblastoma enables the survival of resistant subpopulations, such as glioblastoma stem cells, that evade treatment. Chemotherapy resistance in GBM, particularly to temozolomide, is driven by factors such as O6-methylguanine-DNA methyltransferase upregulation, defective mismatch repair, hypoxia-induced gene expression and activation of several signaling pathways, such as the NF-κB, Hippo and Wnt pathways. Targeted therapies have shown limited success due to activation of compensatory pathways and tumor plasticity, while immunotherapeutic approaches are hindered by an immunosuppressive TME. Recently identified resistance mechanisms, including exosomal transfer of noncoding RNAs and metabolic reprogramming, further complicate treatment. Future directions should emphasize overcoming these challenges through combination therapies, enhanced drug delivery systems and precision medicine approaches. Emerging strategies include targeting persister cells, leveraging metabolic vulnerabilities and integrating AI-driven drug discovery approaches and nanotechnology. Robust patient stratification and biomarker-driven interventions are critical for tailoring therapies and improving outcomes. The present review highlights the urgent need for innovative, multidisciplinary approaches to address the complexity of GBM resistance and advance therapeutic strategies for this lethal disease.