胶质母细胞瘤中通过线粒体失调实现的髓系免疫Warburg劫持

This study aims to illustrate how the Warburg effect drives glioblastoma (GBM) growth and development by dysregulating myeloid mitochondrial dynamics and evading myeloid immunity in the lactate-rich environment. The myeloid immunity is often reprogrammed and suppressed by GBM. A major driver is the lactate-rich, glycolysis-preferred metabolic tumor microenvironment (TME) established by the Warburg effect. Recent studies suggest that the Warburg metabolism shifts tumor-associated myeloid cells (macrophages and microglia) towards an anti-inflammatory, pro-tumorigenic phenotype and promotes glioblastoma growth by immunosuppressing local myeloid defence. Here, we investigate the interplay between the high-lactate acidic TME and myeloid evasion, with a specific focus on lactate-induced disruption of mitochondrial dynamics. We re-analyzed publicly available bulk RNA-sequencing data (GSE216070) from four GBM samples with and without pharmacological lactate inhibition. Glycolytic activity and M2-like myeloid polarization scores were calculated as the mean log 2 (CPM+1) expression of curated hallmark gene sets. The Warburg signatures were then correlated with gene sets reflecting reactive oxygen species regulation and inter- and intra-cellular mitochondrial dynamics. The analysis deciphers how lactate-driven metabolic rewiring of myeloid mitochondria contributes to GBM invasion and immune escape. To further understand how the Warburg effect orchestrates myeloid evasion in GBM, we propose to perform lactate pre-treated, vitamin C (lactate inhibitor) pre-treated and control myeloid cell cultures, then compare their pro-tumorigenic ability via conditioned medium in GBM proliferation and temozolomide chemoresistance assessment. In addition, the pre-treated myeloid cells will be seeded on the opposite side of μ-Dishes with GBM cells in between, to observe if there is any preferential growth or invasion towards either side under live-cell confocal imaging. The mitochondrial dynamics of the pre-treated cells will also be studied through Western blot and flow cytometry. Preliminary results showed high levels of M2-like immunosuppression, reactive oxygen species mechanism and mitochondrial dynamics and surveillance under the Warburg glycolysis environment. With the poor overall survival rate of high-LDHA patients from the Kaplan-Meier curve, the Warburg metabolism serves as a promising therapeutic target. Our study elucidates how Warburg metabolism promotes GBM immune evasion and invasion by inducing mitochondrial dysregulation in brain myeloid cells via the lactate-rich tumor microenvironment.