Stroke drives glioma progression through remodeling of the tumor microenvironment [scRNA-Seq]

Epidemiological studies suggest increased brain tumor risk in patients with prior stroke. Comparative transcriptomic analyses reveal enrichment of stroke-associated gene signatures in high-grade gliomas; nevertheless, the mechanisms that unify these conditions remains unclear. Here we show that stroke promotes tumor infiltration towards the site of stroke injury in human and mouse glioma models, accompanied by reduced overall survival. Stroke induces remodeling of the tumor microenvironment (TME), including the emergence of a unique population of tumor-associated astrocytes (TAAs) that exhibit reduced Ca2+ activity at the infiltrative edge, and enrichment of tumor-associated microglia and macrophages (TAMs). Chemogenetic stimulation of Ca2+ signaling in TAAs or depletion of TAMs reverses stroke-induced glioma progression. We further identify the sodium–bicarbonate cotransporter Slc4a4 as a key regulator of Ca2+ activity in TAAs and associated TAM recruitment. Collectively, our findings demonstrate that stroke accelerates glioma progression through remodeling of astrocytic and immune compartments of the TME.