Glioblastoma 2025: What Every Clinician Needs to Know About the Deadliest Brain Cancer
A comprehensive 2025 review synthesizes GBM epidemiology, molecular drivers, WHO CNS5 classification, diagnostics, and emerging therapies in one authoritative resource.
Summary
Glioblastoma (GBM) remains the most aggressive primary brain tumor in adults, with median survival of only 14–18 months despite maximal therapy. This 2025 review consolidates current knowledge across epidemiology, WHO CNS5 molecular classification, key genetic drivers (IDH-wt, EGFR, TERT, PTEN, TP53), advanced imaging, liquid biopsy, and emerging treatments including immunotherapy, oncolytic virotherapy, and Tumor Treating Fields. The IDH-wildtype designation now anchors GBM diagnosis, with TERT promoter mutation, EGFR amplification, and +7/−10 chromosomal signature serving as defining molecular criteria. Despite breakthroughs in molecular diagnostics and personalized medicine, recurrence is nearly universal, driven by tumor heterogeneity, cancer stem cells, and an immunosuppressive microenvironment. AI-assisted radiomics and next-generation sequencing are identified as transformative tools for improving prognostic stratification and treatment decisions.
Detailed Summary
Glioblastoma multiforme (GBM) accounts for approximately 45–50% of all adult gliomas and carries a five-year survival rate below 5%. This 2025 narrative review synthesizes the full landscape of contemporary GBM science, drawing on literature published between 2018 and 2025, and represents one of the most comprehensive post-WHO CNS5 overviews available.
The 2021 WHO CNS5 classification fundamentally redefined GBM, restricting the diagnosis to IDH-wildtype, adult-type diffuse astrocytic tumors that harbor at least one of three molecular aberrations: TERT promoter mutation, EGFR amplification, or combined +7/−10 chromosomal loss/gain. Tumors with IDH mutations—even those histologically resembling GBM—are now classified separately as astrocytoma IDH-mutant grade 4, reflecting their meaningfully better prognosis. This molecular repositioning has cascading implications for clinical trial design, therapeutic eligibility, and prognostic counseling.
Molecular pathogenesis is multifactorial. EGFR amplification and TERT promoter mutations promote uncontrolled proliferation and cellular immortality. Loss-of-function mutations in PTEN and CDKN2A/B disable tumor suppression. TP53 dysregulation further destabilizes genomic integrity. Epigenetic reprogramming—including global DNA methylation shifts, histone modifications, and chromatin remodeling—drives phenotypic plasticity, enabling tumor cells to switch between proneural and mesenchymal states. Single-cell RNA sequencing data confirm that GBM is not a single disease but a dynamic ecosystem of coexisting subclones occupying distinct niches (hypoxic zones, perivascular regions, GSC-enriched areas), each responding differently to therapy and fueling recurrence through selective clonal expansion.
Diagnostically, MRI remains the gold standard, with advanced modalities (perfusion MRI, DWI/DTI, ¹H-MRS, fMRI tractography) informing surgical planning and tumor characterization. PET with amino acid tracers (¹¹C-methionine, ¹⁸F-FDOPA) differentiates true recurrence from treatment-related pseudoprogression. Liquid biopsy—detecting circulating tumor DNA and exosomes—offers a minimally invasive window for monitoring minimal residual disease and resistance emergence. Radiogenomics and AI-assisted radiomics are emerging as powerful tools linking imaging phenotypes to molecular subtypes, potentially enabling non-invasive genotyping and early treatment response prediction.
Therapeutically, the Stupp protocol (maximal safe resection + concurrent temozolomide + radiotherapy, followed by adjuvant temozolomide) remains standard of care. MGMT promoter methylation status is the principal predictive biomarker for temozolomide benefit. Bevacizumab offers modest benefit at recurrence. Tumor Treating Fields (TTFields) demonstrate a survival benefit when added to standard therapy. Investigational strategies—including cancer vaccines, PD-1/PD-L1 checkpoint inhibitors, CAR-T cell therapies targeting EGFRvIII and IL13Rα2, and oncolytic virotherapy—show preclinical and early clinical promise but have yet to demonstrate definitive survival gains in phase III trials, partly due to GBM's profoundly immunosuppressive tumor microenvironment.
Key Findings
- WHO CNS5 restricts GBM to IDH-wildtype tumors with TERT mutation, EGFR amplification, or +7/−10 signature.
- Median survival remains 14–18 months; 5-year survival is below 5% despite multimodal therapy.
- Single-cell sequencing reveals GBM as a fluid ecosystem of subclones driving therapy resistance and recurrence.
- Liquid biopsy and AI-assisted radiomics are transforming non-invasive monitoring and molecular stratification.
- CAR-T, checkpoint inhibitors, oncolytic virotherapy, and TTFields show promise but lack phase III validation.
Methodology
This is a comprehensive narrative review of literature published between 2018 and 2025, focusing on WHO CNS5 updates, molecular biomarkers, and emerging diagnostics and therapeutics. No systematic search protocol or meta-analytic methodology is reported; inclusion was based on author selection of relevant studies.
Study Limitations
As a narrative rather than systematic review, selection bias in included studies cannot be excluded. Most novel therapeutic strategies (CAR-T, vaccines, oncolytic virotherapy) are evaluated only in early-phase trials, limiting conclusions about efficacy. The review's rapid literature synthesis may not capture all nuances of conflicting evidence across studies.
Enjoyed this summary?
Get the latest longevity research delivered to your inbox every week.