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Genetic drivers such as TP53 loss or breast cancer gene 1 (BRCA1) mutations not only promote genomic instability but also elevate the cellular ROS set-point, forcing the tumor to adopt robust antioxidant adaptations that are absent in infiltrating immune cells [91, 92]

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Also, itaconate is increasingly produced by macrophages with a disrupted TCA cycle - as shown upon LPS stimulation (Strelko et al., 2011) - but triggers subsequently protective effects, e.g., by the inhibition of succinate dehydrogenase (which controls levels of pro-inflammatory succinate), glycolysis and pro-inflammatory NLRP3 inflammasome activation (Strelko et al., 2011), whereas activating the anti-inflammatory transcription factors NRF2 and ATF3 (Peace and ONeill, 2022)

These molecular subtypes not only highlight the heterogeneity of GBM but also provide potential targets for precision medicine