Molecular drivers of epithelial-mesenchymal transition (EMT) in glioblastoma and impact on therapy resistance

Glioblastoma (GBM) is among the most common and aggressive forms of brain tumor and presents a formidable clinical challenge due to its infiltrative nature, recurrence, and resistance to the conventional therapies. The recent evidence has highlighted the function of epithelial-mesenchymal transition (EMT) in driving a number of malignant and aggressive features of GBM. The present review comprehensively investigates the molecular mechanisms underlying EMT in GBM, emphasizing its implications to the tumor metastasis, therapeutic resistance, and potential for localized metastasis within the central nervous system. The key pathways, including TGF-β, Wnt/β-catenin, PI3K/AKT, and Notch, are able to regulate EMT by promoting mesenchymal traits, cellular plasticity, and stemness, facilitating tumor progression and immune evasion. A number of transcription factors such as Snail, Slug, Twist, and ZEB1/2, alongside regulatory non-coding RNAs are involved reinforcing the complexity of EMT modulation in GBM. Furthermore, this review highlights the novel therapeutic interventions targeting EMT, including natural compounds, immunotherapy combinations, and nanoparticle-based delivery systems designed to overcome the blood-brain barrier and minimize systemic toxicity. There will be also a special focus on the function of EMT in the regulation of chemoresistance, particularly to temozolomide, and how pharmacological agents such as 20(S)-Rg3, quercetin, and honokiol suppress EMT. Integrative therapeutic strategies combining EMT inhibition with immune modulation and targeted drug delivery are proposed as promising candidates for enhancing GBM patient outcomes. By elucidating the intricate regulatory networks of EMT, this review would highlight the development of precision therapies capable of mitigating GBM's aggressive behavior and improving long-term survival.