A High-Throughput Screen on Primary Glioblastoma-Associated Macrophages Identifies HDAC Inhibitors as Enhancers of Phagocytosis and Potent Partners for Immunotherapy [CUT&Tag]

HDAC inhibitors, particularly Pracinostat and Resminostat, emerged as potent enhancers of phagocytosis, demonstrating synergy with CD47 blockade across multiple primary human TAM-GBM combinations.

In a xenograft GBM model, Pracinostat suppressed tumor growth and extended survival with additive benefit when combined with CD47 antibodies. RNA-seq and H3K27Ac CUT&Tag profiling of Pracinostat-treated TAMs in vivo revealed a two-tier mechanism: transcriptional reprogramming toward a pro-inflammatory state via NF-kB activation, and epigenetic priming of FcgR-mediated phagocytic machinery, providing a mechanistic basis for the observed synergy with CD47 blockade.