Crosslink Between Neuroinflammation and Oxidative/Nitrosative Status in the Glioblastoma Tumor Microenvironment: Prognostic and Theranostic Impact.

Abstract

Glioblastoma (GB) is the most aggressive primary brain tumor, characterized by rapid progression, therapeutic resistance, and poor prognosis. Increasing evidence suggests that oxidative and nitrosative stress, together with a proinflammatory tumor microenvironment (TME), play a critical role in gliomagenesis. In this study, we analyzed a cohort of 89 Algerian patients with GB glioblastoma, to characterize systemic and intratumoral oxidative/ nitrosative status. Hydrogen peroxide, malondialdehyde, total nitrite levels, and catalase activity were quantified in serum or plasma, cystic fluid, and tumor homogenates to assess redox balance across different histological glioblastoma subtypes. In parallel, tumor expression of proinflammatory cytokines: interleukin-6 (IL-6), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and key mediators of tumor progression: Nuclear factor kappa B p65 (NF-κB p65), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF), was evaluated. Additionally, we investigated the interplay between redox balance and inflammatory signaling, and its potential implications for prognosis and theranostic therapeutic decision-making. Our findings demonstrated systemic and intratumoral redox imbalance in serum/ plasma compared with TME tumor microenvironment compartments, without impact from any subtypes. However, we noted pronounced intratumoral proinflammatory cytokines expression, as well as NF-κB p65, iNOS and VEGF in most cases, consistent with ongoing neuroinflammatory signaling, a highly reactive TME and more aggressive histopathological features. Combined assessment of oxidative/ nitrosative stress biomarkers and proinflammatory cytokines provides valuable insight into GB glioblastoma prognostic relevance. Targeting redox imbalance and inflammatory pathways within the GB glioblastoma TME represents a promising strategy to enhance therapeutic efficacy and improve patient outcomes.