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

This study presents the first high-throughput chemical screen on primary tumor-associated macrophages (TAMs) freshly isolated from surgical glioblastoma (GBM) patient samples, testing 1,365 compounds to identify drugs that enhance TAM phagocytosis. 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.