Disrupted Signalling Landscapes in Glioblastoma: Mechanistic Insights and Therapeutic Frontiers

Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumour, originating from glial cells known as astrocytes and accounting for over 50% of all central nervous system malignancies. Its aetiology is linked to various factors, including radiation exposure, genetic alterations, and viral influences, which trigger the uncontrolled growth and rapid infiltration of glial cells into surrounding brain tissues. Despite standard multidisciplinary management involving maximal safe surgical resection, radiotherapy, and temozolomide, the prognosis remains poor. The molecular landscape of GBM is characterised by profound dysregulation across highly conserved signalling networks, including the PI3K/AKT/mTOR, ERK/MAPK, Wnt/β-catenin, and Hippo pathways. These pathways are frequently hijacked by genetic and epigenetic alterations such as EGFR amplification and PTEN loss, which drive essential hallmarks of cancer like uncontrolled proliferation, angiogenesis, and apoptosis evasion. A defining feature of GBM is its extreme intra-tumoral heterogeneity and cellular plasticity, where tumour cells dynamically transition between distinct transcriptional states, including mesenchymal, astrocyte-like, and neural progenitor-like, to adapt to therapeutic pressures. This complexity is further exacerbated by microenvironmental factors. Clinical progress is severely hindered by the blood–brain barrier (BBB), which restricts systemic agents from reaching invasive tumour margins. Targeted monotherapies, such as EGFR and mTOR inhibitors, have largely failed in clinical trials due to compensatory feedback loops and pathway redundancy. Consequently, the therapeutic paradigm is shifting toward rational combination therapies and novel immunotherapeutic platforms. Emerging strategies, such as bivalent CAR T-cell therapy targeting both EGFRvIII and IL-13Rα2, have shown early clinical promise in achieving tumour regression, highlighting a potential path toward precision medicine. This review synthesises current insights into signalling dysregulation and explores the future frontiers of multi-targeted therapeutic interventions in GBM.