Metabolic licensing of quiescent glioblastoma activation and immune evasion via astrocyte-mitochondria shuttle

The reaction of quiescent tumor cell subpopulations at the invasive margin of glioblastoma (GBM) might be cleared by immune surveillance toward death or expand through immune escape, which can drive therapeutic resistance, tumor dissemination, and recurrence through phenotypic plasticity. However, the process and mechanisms underlying their activation remain largely unclear. This study revealed that astrocytes awaken quiescent GBM cells to cycling and immune-evasive phenotypes. Astrocytic mitochondria are indispensable in regulating the phenotypic changes. Specifically, the SHMT2 enzyme in astrocytic mitochondria catalyzes one-carbon metabolic products, which significantly promote synthetic metabolic activation and reactivation of quiescent GBM cells to immune evasion through intercellular mitochondrial transfer. Tumor cells that acquire astrocytic mitochondria enhanced one-carbon metabolism drives global hyperactive anabolic metabolism through YTHDC1-mediated transcriptional pause release of ribosomal and focal adhesion signaling genes, supporting rapid proliferation and conferring a potent immune-evasive phenotype. Therapeutically, pharmacologic or genetic inhibiting the astrocytic SHMT2 or blocking mitochondrial transfer markedly suppressed quiescent GBM cell activation and tumor progression. These findings elucidate a novel mechanism by which astrocytes in the tumor microenvironment drive GBM malignancy through metabolic symbiosis. Overall design: Glioma was digested and dissociated single-cell suspensions were loaded to scRNA-seq. U87 cells from co-culture system of various groups were sorted using Fluorescence-activated cell sorting (FACS) and analyzed using CUT&Tag seq.