Abstract Glioblastoma (GBM) is a highly aggressive and lethal form of primary brain tumor. Systemic suppression of the immune system, specifically T-cell impairment, significantly contributes to GBM development and progression. Recent advances in cancer immunotherapies have shown great promise in alleviating such tumor-associated immunosuppression, namely programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) checkpoint inhibitors. Regrettably, early clinical studies evaluating the efficacy of checkpoint inhibition in recurrent GBM have rendered only modest improvements in overall survival rates, due partially to insufficient inhibition of AKT-STAT3 pathways which are often dysregulated downstream of hyperactive epidermal growth factor receptors (EGFR) in GBM. In the current study, we aim to evaluate a newly discovered small molecule inhibitor of AKT-STAT3, honokiol, and its ability to suppress AKT-STAT3 activity in the context of hyperactive EGFR in GBM. Using U87-MG cells that stably overexpress a common hyperactivating mutation of EGFR, EGFRvIII, we have preliminary evidence that honokiol is an effective inhibitor of U87-EGFRvIII cellular migration as a result of its robust AKT-STAT3 pathway suppression. Thus, honokiol may provide a novel means of pharmacological inhibition of AKT-STAT3 hyperactivity in GBM and therefore greater clinical efficacy of immune checkpoint inhibitors in this deadly disease. Citation Format: Keller Smith, Blake Johnson. Examining the effects of honokiol on EGFR-positive glioblastoma multiforme [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5182.