Frontiers in glioblastoma therapy: Novel therapeutics, molecular pathways, and future clinical perspectives

Abstract

Glioblastoma (GBM) remains one of the most aggressive and therapy-refractory primary brain tumors, with patient survival exhibiting only marginal gains despite decades of intensive research and therapeutic advancement. Standard-of-care interventions, including maximal surgical resection, radiotherapy, and the alkylating agent temozolomide, confer only modest clinical benefit. The limited therapeutic efficacy is primarily attributed to pronounced intra- and intertumoral heterogeneity, the persistence of therapy-resistant glioblastoma stem-like cells, and the restrictive nature of the blood–brain barrier (BBB), which collectively impede durable treatment responses. These therapeutic challenges have intensified efforts to develop novel treatment strategies for glioblastoma. Recent advances in preclinical research increasingly leverage patient-derived stem cell and organoid models, which more faithfully recapitulate the molecular and phenotypic heterogeneity of human tumors and enable the identification of broadly effective therapeutic vulnerabilities. Emerging approaches include the exploration of histone deacetylase (HDAC) inhibitors, cyclin-dependent kinase (CDK) inhibitors, and other rationally designed small-molecule agents. In parallel, innovative drug delivery platforms such as nanoparticle-based formulations, convection-enhanced delivery, and focused ultrasound are being actively investigated to enhance blood–brain barrier permeability and improve intra-tumoral drug distribution. Emerging therapeutic modalities, including immunotherapies such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and cancer vaccines, together with oncolytic virotherapy and gene-editing technologies, are broadening the therapeutic landscape of glioblastoma. This review synthesizes current advances in preclinical and translational research, emphasizing how the convergence of personalized medicine, multi-targeted pathway inhibition, and next-generation delivery platforms may collectively enhance therapeutic efficacy and ultimately improve patient survival. © 2025 Elsevier B.V.