Abstract Glioblastoma (GBM) progression is driven in large part by dynamic interactions between tumor cells and the myeloid compartment within a mechanically stressed tumor microenvironment (TME). Tumor-associated macrophages (TAMs) and microglia (MG) undergo functional reprogramming in response to biophysical and epigenetic cues, often to support the tumor (e. g. , pro-tumor, anti-inflammatory, M2-like). However, the mechanisms by which tumor growth-induced mechanical compression – exerted both within and outside of the tumor microenvironment – impacts immune polarization and its effects on GBM invasion remains poorly defined. To investigate the effects of mechanical compression, we performed in vitro studies on human myeloid-derived macrophages and MG polarized to M0- (e. g. , unpolarized), M1- (e. g. , anti-tumor, pro-inflammatory), and M2-like states using GBM-conditioned media and co-culture invasion assays with human U87 GBM cells. Mechanical compression – using our established transwell system that mimics GBM growth-induced forces – significantly enhanced tumor invasion, with M2-like associated cultures inducing greater invasion than M1- or M0-like. Pharmacological histone deacetylase (HDAC) inhibition with CAY10603 (HDAC6 inhibitor) markedly reduced invasion in MG-mediated conditions. In TAMs, compression increased TNFα and IL1B gene expression in M1-like cells, while TGFβ and MMP1 were upregulated in M0-like cells. In MG, compression broadly induced pro-invasive gene programs, including increased MMP1, MMP9, and CCL2 across all polarization states. IL6 and IL1B were elevated in compressed M0- and M1-like microglia, whereas TNFα was selectively increased in M0-like microglia. Additionally, phagocytosis assays demonstrated that HDAC inhibitors (CAY10603 and SAHA pan-HDAC inhibitor) significantly enhanced macrophage-mediated particle engulfment, with CAY10603 inducing the strongest response in both M0- and M2-like macrophages that was comparable with anti-CD47 antibody induction. To increase translational relevance of these findings, we grew patient-derived organoid (PDO) GBM models, in which treatment with CAY10603 and SAHA significantly reduced viability in PDO, PDO/monocyte, PDO/TAM-M0 and PDO/MG co-cultures, exceeding the cytotoxic effects of the standard chemotherapy temozolomide (TMZ). Notably, CAY10603 also reduced PDO solidity and circularity, indicating disrupted tumor structural integrity and growth dynamics. Our findings implicate tumor-growth induced mechanical compression as a driver of epigenetic immune reprogramming in GBM and highlight mechano-epigenetic targeting as a novel promising therapeutic strategy. Citation Format: Golnaz Asaadi Tehrani, Jenna Collier, Lauren Gascon, Joshua Kim, Meenal Datta. Mechano-Epigenetic Reprogramming of Myeloid Cells Suppresses Glioblastoma Invasion and Restores Phagocytic Function abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr A015.
Tehrani et al. (Mon,) studied this question.