Abstract 6581: Reprogramming microglial and GAMs phenotype and function, with HDAC inhibitors to overcome immune suppression in glioblastoma

Abstract Glioblastoma multiforme (GBM) stands as the most aggressive form of primary tumor in the central nervous system, primarily affecting older male individuals. The immune landscape in GBM is significantly influenced by Glioma-associated microglia and infiltrating macrophages (GAMs), which together account for up to 45% of the tumor mass. These cells are highly plastic and can shift their phenotype between tumor-fighting, pro-inflammatory (M1-like) and tumor-supportive, anti-inflammatory (M2-like) states in response to different environmental cues. Epigenetic regulation of this plasticity has emerged as a promising therapeutic strategy to reprogram innate immunity within the TME. Here, we demonstrated that selective class IIb HDAC inhibitor treatment reprograms primarily macrophages and microglia toward a pro-inflammatory, phagocytic, and tumor-killing state. Using the BV2 microglial cell line and bone marrow-derived macrophages, we found that HDAC class IIb inhibitors increased M1 markers, decreased M2 phenotype, and enhanced phagocytosis. Interestingly, they enhanced microglial migration in both M1-like and M2-like cells, potentially reflecting the innate migratory capacity of these resident immune cells in the brain, which are constantly surveilling and rapidly responding to environmental cues. In contrast, these class IIb inhibitors reduced macrophage migration, underscoring the functional divergence between these cell types. To further validate our findings in a physiologically relevant system, we optimized a robust high-purity primary microglia isolation protocol from murine brains. Future work includes transcriptomic profiling and in vivo studies to assess therapeutic efficacy and immune remodeling. Our results support HDAC class IIb inhibition as a promising strategy to modulate immune responses in GBM and suggest that targeting myeloid cell plasticity may enhance the efficacy of immunotherapeutic responses in GBM. Citation Format: Sonia Sebaoui. Reprogramming microglial and GAMs phenotype and function, with HDAC inhibitors to overcome immune suppression in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6581.