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P036: GENETIC DRIVERS OF ENERGETIC REPROGRAMMING AND IMMUNE ESCAPE IN GLIOBLASTOMA
Jawad A Saad, BS; James Chung, BS; Ahmad Kafri, BS; Julien Rossignol, PhD; Maxwell Verbrugge, MD; Jesse Bakke, PhD; Central Michigan University College of Medicine

Introduction: Glioblastoma (GBM) is a devastating central nervous system malignancy characterized by complex genetic and molecular aberrations. GBMs pathogenesis and aggressive nature is profound metabolic reprogramming. GBM cells exhibit the "Warburg effect," a preferential reliance on aerobic glycolysis. This metabolic shift, driven by genetic alterations and the tumor microenvironment (TME), shaped GBM's resilience and adaptability.

This study aims to comprehensively synthesize the critical metabolic pathways, major genetic drivers, and functional consequences, including adaptability and immune evasion, that define the aggressive phenotype of GBM, highlighting their potential as therapeutic targets.

Methods: A narrative review was conducted, synthesizing 152 peer-reviewed publications from January 2000 to September 2025 across basic, translational, and clinical studies. Literature was identified through PubMed, Embase, and Web of Science using combinations of keywords including glioblastoma, metabolism, IDH mutation, 2-hydroxyglutarate (2-HG), aerobic glycolysis,pseudohypoxia, PI3K/Akt/mTOR, EGFR, immune resistance, tumor-associated macrophage (TAM), M2 polarization, T-cells, and oxidative phosphorylation (OXPHOS). Reference lists of key articles were also reviewed to capture additional publications. Eligible studies included English-language articles focused on GBM, encompassing preclinical models, translational work, and clinical trials, while excluding single case reports and non-primary brain tumor studies. Findings were synthesized thematically, with this section of the study focusing on major metabolic pathways, genetic drivers, and the resulting tumor-host interactions, including metabolic flexibility and immune resistance, observed in GBM.

Results: Genetic alterations profoundly shape glioblastoma energetics, exemplified by IDH mutations that generate the onco-metabolite 2-HG, drive tumorigenic phenotypes, and induce ‘pseudohypoxia’ through inhibition of α-ketoglutarate (α-KG)-dependent enzymes, resulting in stabilization of HIF-1α and VEGF. However, the majority of GBMs are IDH wild-type, where dysregulation often involves EGFR amplification or PTEN loss, activating the PI3K/Akt/mTOR pathway and increasing HIF-1α. HIF-1α stabilizes under hypoxic stress and remains active in normoxic settings via pathways like PI3K/AKT/mTOR, upregulating glycolytic genes like GLUT1, HK2, and LDHA. This accelerated glycolysis generates lactate, which provides critical metabolic flexibility by enabling interconversion between aerobic glycolysis and oxidative phosphorylation (OXPHOS) across tumor regions via MCT1 and MCT4 transporters. Lactate also promotes immune evasion by acidifying the TME, polarizing macrophages and microglia toward the pro-tumor M2 phenotype (upregulating ARG1 and VEGF), and enhancing the immunosuppressive function of Regulatory T-cells (Tregs) by increasing CTLA-4 expression. Additionally, glutaminolysis is vital for anabolism, replenishing OXPHOS intermediates (anaplerosis), and producing NADPH for lipid synthesis. Fatty acid and cholesterol synthesis are also upregulated, driven by enzymes like FASN, ACC, and transcriptional regulator SREBP2. Notably, a distinct GBM subtype relying on mitochondrial dominance and elevated OXPHOS activity has been identified, correlating with improved patient survival.

Conclusion: GBM survival and proliferation depend on a complex, flexible metabolic framework that links oncogenic signaling, enhanced anabolism (glycolysis, glutaminolysis, lipogenesis), and TME dynamics. The constitutive activity of HIF-1α and the immunosuppressive effects of tumor-derived lactate present critical vulnerabilities. Therapeutic strategies must address this heterogeneity, potentially by targeting specific metabolic enzymes (e.g., GLS, ACC) or through novel approaches that interfere with hypoxia signaling, lactate transport, or the distinct OXPHOS phenotype.

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