Valproic acid reverses macrophage-mediated temozolomide resistance in macrophage-rich gliomas

Glioma therapy often fails due to the acquisition of temozolomide (TMZ) resistance. Antiepileptic drugs, valproic acid (VPA) and levetiracetam (LEV) are commonly used during the perioperative period of glioma patients, and have been proposed for repurposing to augment TMZ efficacy. Our previous studies revealed that LEV could increase TMZ efficacy through downregulation of O-6-methylguanine-DNA methyltransferase (MGMT) and VPA could promote glioma cells apoptosis. Recently, tumor-associated macrophages (TAMs) have been considered as important modulators of TMZ resistance. As for LEV or VPA, which one is better to improve TMZ efficacy for macrophage-rich gliomas remains unclear. In this study, we investigated whether VPA or LEV could mitigate macrophage-mediated exceptional TMZ resistance. Our in vitro experiments revealed that VPA rather than LEV could polarize TAMs into M1 phenotypes. In vivo, glioma mouse models could benefit more from TMZ + VPA regimen by increasing intratumoral M1 macrophage infiltration. We conclude that VPA might be more useful than LEV to improve the therapeutic effect of TMZ for macrophage-rich gliomas. This study provides critical preclinical evidence for the optimal selection of the antiepileptic drug to overcome TAM-mediated chemoresistance, offering translational implications for personalized therapeutic strategies for macrophage-rich gliomas.