Metabolic and epigenetic dysregulation in IDH1/2-mutant gliomas: A microglial-mediated mechanism of blood-brain barrier disruption.

Gliomas are a group of highly invasive and recurrent tumors originating from neural stem cells or glial progenitor cells. According to data from the Central Brain Tumor Registry of the United States published in 2023, the global incidence of gliomas is estimated at approximately 2.53 per 100,000 individuals(Ostrom et al., 2023. Although surgical resection remains the primary treatment strategy, the 2021 WHO Classification of Tumors of the Central Nervous System reports that the five-year survival rate for gliomas typically ranges from 80 % to 90 %, whereas low-grade gliomas with IDH-wildtype mutations have a five-year survival rate of approximately 50 % to 60 %(Louis et al., 2021. Therefore, IDH1/2 mutations are widely considered favorable prognostic markers in gliomas. However, recent studies have indicated that, compared to IDH-wildtype gliomas, IDH1/2-mutant gliomas often exhibit a significant reduction in survival time and a marked deterioration in prognosis following progression or recurrence. This suggests that, even for molecular subtypes with initially favorable prognoses, progression to a higher-grade state, their biological behavior may rapidly shift toward that of more aggressive gliomas, and may be accompanied by varying degrees of blood-brain barrier (BBB) disruption. This review aims to comprehensively examine the association between IDH1/2 mutations and BBB disruption, elucidating how IDH1/2-mutant gliomas alter tumor-associated metabolic and epigenetic pathways, which subsequently influence microglial activation and polarization, contributing to BBB impairment. Furthermore, we propose that microglia-mediated BBB disruption may be one of the underlying mechanisms contributing to complications in IDH1/2-mutant gliomas, such as vasogenic edema and immune-mediated encephalopathy, both of which are closely associated with BBB breakdown.