An update on the molecular biology of glioblastoma, with clinical implications and progress in its treatment.

Glioblastoma multiforme (GBM) is the most aggressive and common malignant primary brain tumor. Patients with GBM often have poor prognoses, with a median survival of ∼15 months. Enhanced understanding of the molecular biology of central nervous system tumors has led to modifications in their classifications, the most recent of which classified these tumors into new categories and made some changes in their nomenclature and grading system. This review aims to give a panoramic view of the last 3 years' findings in glioblastoma characterization, its heterogeneity, and current advances in its treatment. Several molecular parameters have been used to achieve an accurate and personalized characterization of glioblastoma in patients, including epigenetic, genetic, transcriptomic and metabolic features, as well as age- and sex-related patterns and the involvement of several noncoding RNAs in glioblastoma progression. Astrocyte-like neural stem cells and outer radial glial-like cells from the subventricular zone have been proposed as agents involved in GBM of IDH-wildtype origin, but this remains controversial. Glioblastoma metabolism is characterized by upregulation of the PI3K/Akt/mTOR signaling pathway, promotion of the glycolytic flux, maintenance of lipid storage, and other features. This metabolism also contributes to glioblastoma's resistance to conventional therapies. Tumor heterogeneity, a hallmark of GBM, has been shown to affect the genetic expression, modulation of metabolic pathways, and immune system evasion. GBM's aggressive invasion potential is modulated by cell-to-cell crosstalk within the tumor microenvironment and altered expressions of specific genes, such as ANXA2, GBP2, FN1, PHIP, and GLUT3. Nevertheless, the rising number of active clinical trials illustrates the efforts to identify new targets and drugs to treat this malignancy. Immunotherapy is still relevant for research purposes, given the amount of ongoing clinical trials based on this strategy to treat GBM, and neoantigen and nucleic acid-based vaccines are gaining importance due to their antitumoral activity by inducing the immune response. Furthermore, there are clinical trials focused on the PI3K/Akt/mTOR axis, angiogenesis, and tumor heterogeneity for developing molecular-targeted therapies against GBM. Other strategies, such as nanodelivery and computational models, may improve the drug pharmacokinetics and the prognosis of patients with GBM.