TMIC-65. Polyamine acetylation bridges tumor and immune cell metabolism in glioblastoma

Abstract Metabolic reprogramming in cancer cells not only sustains proliferative signaling but also modulates the anti-tumor immune response via secretion of immunomodulatory metabolites. Polyamines are small, positively charged metabolites synthesized from the urea cycle intermediate ornithine. While inhibition of polyamine synthesis has emerged as a target in cancer therapy, whether rewiring of polyamine metabolism in tumor cells impacts the tumor immune microenvironment remains unclear. Here, we find that polyamine acetylation is elevated in human and murine glioblastoma (GBM) tumors and demonstrate that tumor cell-derived N1-acetylspermidine can be taken up by myeloid cells to promote intracellular polyamine flux, cellular respiration and migration. Using a genetic model of GBM, deletion of the polyamine acetylation enzyme SAT1 (spermidine/spermine-N1-acetyltranferase1) reduced the metabolic activity of tumor cells, impeded myeloid infiltration and sensitized tumors to chemoradiation. Collectively, our findings highlight a previously unidentified role for spermidine acetylation, secretion and uptake in bridging the metabolic activity of tumor cells and myeloid cells, together, promoting mesenchymal/plurimetabolic states and therapeutic resistance in GBM.