**3.3 Small molecule inhibitor**

Myeloid-derived suppressor cells (MDSCs) have been shown to be expanded in the periphery of GBM patients [144]. MDSCs within the TME have been shown to contribute to tumor immunosuppression via the secretion of immunosuppressive molecules such as arginase 1 and inducible nitric oxide synthase (iNOS). Alban *et al.* expanded upon these findings and found the monocytic subset of MDSCs (mMDSCs) express high levels of CD74 and its ligand, macrophage migration inhibitor factor (MIF). They used MN-166, a small molecule inhibitor of phosphodiesterase capable of penetrating the blood-brain barrier to inhibit the CD74/MIF interaction on myeloid cells and therefore prevent mMDSC formation. They found MN-166-treated MDSCs prevented MDSC-mediated T cell suppression. In addition, increased intratumoral CD8<sup>+</sup> T cells were found when tumor-bearing mice were treated with MN-166. Despite no difference in survival being observed, the authors suggest this therapy could combine well with activating immunotherapies [145].

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor shown to be upregulated in GBM and is correlated with decreased survival. Wightman *et al.* have shown treatment of GBM cells with IL-6 increased phosphorylation and overall STAT3 expression. The authors used bazedoxifene, a selective estrogen receptor modulator, to inhibit IL-6-mediated STAT3 activation. Importantly, they show treatment of GBM cells with bazedoxifene decreases markers of GSCs, such as SRY-box transcription factor 2 (SOX2) and octamer-binding transcription factor 4 (OCT4). In addition, they demonstrate treatment of tumorbearing mice with bazedoxifene significantly prolongs survival relative to vehiclecontrol treated mice [146].
