Renee D. Read1,2,3, Zoe M. Tapp4, Prajwal Rajappa4,5,6 and Dolores Hambardzumyan7,8 1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA; 2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia 30322, USA; 3Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA; 4The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA; 5Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, Ohio 43215, USA; 6Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio 43215, USA; 7Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA; 8Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA Corresponding authors: dolores.hambardzumyanmssm.edu, renee.reademory.edu, prajwal.rajappanationwidechildrens.org Abstract

Glioblastoma (GBM) is the most aggressive primary brain cancer. These tumors exhibit high intertumoral and intratumoral heterogeneity in neoplastic and nonneoplastic compartments, low lymphocyte infiltration, and high abundance of myeloid subsets that together create a highly protumorigenic immunosuppressive microenvironment. Moreover, heterogeneous GBM cells infiltrate adjacent brain tissue, remodeling the neural microenvironment to foster tumor electrochemical coupling with neurons and metabolic coupling with nonneoplastic astrocytes, thereby driving growth. Here, we review heterogeneity in the GBM microenvironment and its role in low-to-high-grade glioma transition, concluding with a discussion of the challenges of therapeutically targeting the tumor microenvironment and outlining future research opportunities.