Review of glioblastoma and systemic comorbidities.

Glioblastoma (GBM) is a highly aggressive malignancy with a poor prognosis. Despite advanced molecular characterization, the traditional tumor-centric model ignores the patient's systemic body condition, which significantly influences disease progression and therapeutic outcomes. This review aims to elucidate the interactions between GBM and systemic comorbidities, focusing on metabolic, immune, and vascular networks. A key feature is activity-dependent gliomagenesis, in which neuronal firing via Neuroligin-3 (NLGN3) and glutamatergic signaling fuels tumor growth. This process confers a substantial cognitive reserve, thereby attenuating or masking early clinical manifestations via functional compensatory mechanisms; however, it may concomitantly promote rapid tumor proliferation. Overall, combined diabetes, glutamine-induced and hyperglycemia or dexamethasone-induced hyperglycemia may trigger tumor aggressive. The prothrombotic nature of GBM complicates the use of anti-angiogenic therapies. Thus, GBM and its comorbidities can be seen as metabolic-immune and vascular-cardiovascular cycles. Furthermore, chronic Hepatitis B (HBV) infection poses a unique risk of fatal reactivation during therapy in endemic regions, such as China. Consequently, real-world GBM management requires a shift from an isolated oncological to a patient-centric approach. Addressing systemic health disparities and the intrinsic interplay of comorbidities is essential to optimize treatment protocols and improve patient survival.