Microenvironment-derived acetylated amino acids promote glioblastoma treatment resistance

Abstract Rapid repair of genotoxic therapy induced DNA damage mediates treatment resistance in glioblastoma (GBM). The role of non-malignant cell types in the tumor microenvironment in accelerating DNA repair in neoplastic cells is poorly understood. Using spatial transcriptomics, immunofluorescence, metabolomics, patient tissues and preclinical models, we show that tumor associated macrophages (TAMs) in GBM promote DNA repair and treatment resistance in neoplastic cells through the secretion of acetylated amino acids. These acetylated amino acids are consumed by GBM cells, leading to enhanced acetyl Co-A levels, histone acetylation and nucleotide synthesis. Interrupting histone acetylation via inhibition of the acetyltransferase KAT5 breaks these metabolic links and reverses the protective capacity of microenvironment-derived acetylated amino acids and TAMs. Blocking the exchange of acetylated amino acids and their downstream effects is a potential strategy for the treatment of GBM.