Glioblastoma in the post-2021 era: Diagnostic recalibration, therapeutic innovations, and future horizons

Abstract

Glioblastoma (GBM) remains a devastating diagnosis, and since 2021, the field has witnessed both incremental advances and renewed paradigms in diagnosis, therapeutic development, and trial design. The 2021 WHO Central Nervous System 5 classification redefined GBM as isocitrate dehydrogenase (IDH)-wildtype, sharpening the molecular underpinnings of clinical trial cohorts. Targeted approaches in selected molecular subsets (e.g., IDH inhibitors) have matured, while tumor-treating fields remains a debated but utilised adjunct. Immunotherapy via checkpoint inhibitors has been disappointing in unselected populations, but newer vaccines, oncolytic viral, and combination strategies are under active development. The most hopeful advances in the 2023-2025 window come from engineered cell therapies, especially chimeric antigen receptor T-cell delivered locoregionally or with multivalent antigen specificity. Advances in liquid biopsy, spatial transcriptomics, imaging biomarkers, and adaptive trial platforms are converging to accelerate translation. This narrative review synthesises developments since 2021, integrating translational insight and practical guidance, and outlines a roadmap for the next decade of GBM research.

Keywords: Glioblastoma; Chimeric antigen receptor T-cell therapy; Tumor treating fields; Immunotherapy; Radiotherapy, molecular diagnostic techniques

Core Tip: The management of glioblastoma (GBM) has entered a post-2021 era characterized more by convergent advances in molecular classification, trial design, and immunoengineering than by a single therapeutic breakthrough. The 2021 WHO Central Nervous System 5 redefinition of GBM as an isocitrate dehydrogenase-wildtype entity has altered clinical trial interpretation, diagnosis, and prognosis. Molecularly selected targeted therapies, improved tumor treating fields, and a deliberate shift away from ineffective single-agent immunotherapy toward combinatorial and neoadjuvant approaches are driving incremental progress, even though conventional chemoradiation continues to be the cornerstone of care. Locoregionally administered, multivalent engineered cell therapies, along with developments in liquid biopsy, spatial profiling, and adaptive platform trials, provide the most convincing indications of future impact. When taken as a whole, these advancements highlight a move in GBM treatment paradigms toward precision-guided, biologically informed, and adaptive approaches.