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

Reactivating quiescent tumor cells at the invasive margin are either eliminated by immune surveillance or expand through immune escape. The mechanisms underpinning phenotypic plasticity driving expansion leading to therapeutic resistance, dissemination, and recurrence remain elusive. Here we establish a metabolic licensing paradigm wherein reactive astrocytes awaken dormant glioblastoma cells and simultaneously confer immune evasion through intercellular mitochondrial transfer. Astrocyte-derived mitochondria, enriched with the one carbon metabolism enzyme SHMT2, deliver functional metabolic units that reprogram recipient glioma cells. This shuttled cargo fuels S adenosylmethionine production, driving m⁶A RNA methylation and release of paused RNA polymerase II over a specific set of genes. Ribosome biogenesis and focal adhesion pathways are selectively upregulated consequently, which enables rapid proliferation and immune resistance of tumour cells. Genetic ablation of astrocytic Shmt2 or pharmacological blockade of mitochondrial transfer suppresses quiescent cell reactivation and delays tumor progression. Our findings thus establish the astrocyte-mitochondria shuttle as a core vulnerability in glioblastomas, linking metabolic crosstalk to epitranscriptomic control of reactivation and immune escape.