Abstract A015: Mechano-Epigenetic Reprogramming of Myeloid Cells Suppresses Glioblastoma Invasion and Restores Phagocytic Function

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(6_Suppl):Abstract nr A015.