Enhancement of Antitumor Immunity via the Inhibition of Ferroptosis-mediated Endoplasmic Reticulum Rupture Links IDH Mutation with Glioma Prognosis

Objective Ferroptosis, an iron-dependent programmed cell death, results in poor glioma prognosis via the suppression of anti-tumor immunity. Given that Ca ²⁺ stored in the endoplasmic reticulum plays an important role in immune signaling, and the endoplasmic reticulum is a key target of ferroptosis, we tested the hypothesis that IDH mutation enhances anti-tumor immunity via the inhibition of ferroptosis-mediated endoplasmic reticulum rupture thereby improving prognosis. Methods Survival analysis, mRNA expression analysis, and ssGSEA were conducted on TCGA and CGGA data. Results Gene sets indicative of oxidative stress and ferroptosis were significantly enriched in IDH wildtype compared to mutant samples. Gene sets associated with Ca ²⁺ homeostasis, immune signaling, and patient survival were affected considerably by IDH mutation. The gene set related to oxidative phosphorylation is enriched in mutant compared to wildtype samples while the gene set for glycolysis is enriched in wildtype compared to mutant samples. SOD2 is highly expressed and has a strong prognostic significance in glioma more than all other tumors. NOX4 in addition to being highly expressed, has the highest prognostic relevance among the five NOX isoforms. Conclusion Mitochondrial O ₂ ^- . Plays an important role in glioma progression. Rather than the ETC, NOX4 could be the major source of O ₂ ^- . during gliomagenesis. IDH mutation reduces oxidative stress and inhibits ferroptosis. In addition, the mutation profoundly affects immune response. It reduces the Warburg effect and also affects intracellular Ca ²⁺ concentration. The effect of the mutation on intracellular Ca ²⁺ concentration and immune signaling suggests that its modulatory function on anti-tumor immunity arises from ferroptosis-mediated endoplasmic reticulum rupture.