Glioblastoma quiescent cells hijack astrocyte-derived mitochondria to drive activation and malignancy

Quiescent tumor cell subpopulations at the invasive margin of glioblastoma (GBM) can drive therapeutic resistance, tumor dissemination, and recurrence through phenotypic plasticity. However, the mechanisms underlying their activation remain unclear. This study reveals that reactive astrocytes regulate this critical process via mitochondrial transfer. Specifically, Shmt2 enzyme in astrocytic mitochondria catalyzes one-carbon metabolic products, which significantly promote synthetic metabolic reprogramming and activation of quiescent GBM cells through intercellular mitochondrial transfer. Mechanistic analyses show that tumor cells acquiring astrocytic mitochondria exhibit two key features: (1) Enhanced one-carbon metabolism drives global hyperactive anabolic metabolism through YTHDC1-mediated transcriptional pause release of ribosomal genes; (2) Acquisition of immune-evasive phenotypes and mesenchymal/astrocyte-like characteristics. Genetic experiments further demonstrate that inhibiting astrocytic mitochondrial serine catabolic enzyme SHMT2 or blocking mitochondrial transfer markedly suppresses 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. 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.