Glioblastoma (GBM) is a uniformly fatal malignancy with limited treatment options. Immune checkpoint blockers (ICBs) have revolutionized the treatment of several malignancies, but have failed in all Phase III trials in newly diagnosed and recurrent glioblastoma (GBM) patients. This limited efficacy of ICBs is due to profound immunosuppression in the GBM tumor microenvironment (TME) caused by paucity of cytotoxic T cells, abundance of regulatory T cells, resident macrophages and microglia and infiltration of myeloid- derived cells from the bone marrow. Wnt signaling fuels GBM progression by aiding proliferation, stemness, epithelial-to-mesenchymal transition and chemoresistance. However, the role of Wnt signaling in immune suppression in GBM is not known. In our preliminary studies we found that Wnt signaling is elevated in murine and human GBMs. A porcupine inhibitor WNT974 -- that blocks Wnt signaling -- in combination with anti-PD-1 antibody (αPD1) prolonged the survival of GBM-bearing mice. This increased survival was accompanied by an expansion of a novel DC3-like dendritic cell state and decrease in granulocytic myeloid- derived suppressor cells (gMDSCs) that may mediate the response to this combination in responding tumors. By contrast, poorly-responding tumors showed an increase in monocytic (m) MDSCs, insufficient T cell infiltration and T cell effector function, suggesting potential resistance mechanisms. Our prior work shows that genetic deletion or pharmacological inhibition of Wnt signaling disrupts the GBM vasculature and makes it leaky. Moreover, ICBs themselves increase edema in GBM patients and require the use of steroids that are highly immunosuppressive. Our preliminary studies show that losartan, an angiotensin receptor blocker, can reduce αPD1-induced edema and reprogram the immunosuppressive TME to an immunostimulatory milieu to favor T cell infiltration and effector function. Building on these exciting findings, our overarching hypothesis is that Wnt signaling reprograms the GBM tumor microenvironment from immune suppressive to immune stimulatory, thus potentiating αPD1 therapy, and adding losartan further enhances the outcome by overcoming treatment resistance mechanisms, and reducing edema. We will test this hypothesis by examining the function of (a) antigen cross-presenting DCs and (b) decreased gMDSCs in mediating the response to WNT974 and αPD1 (Aim 1). We will also test the hypothesis that resistance to WNT974+αPD1 is caused by (a) increased mMDSCs and (b) lack of T cell infiltration and function (Aim 2). In Aim 3, we will test the hypothesis that the combination of losartan with Wnt-inhibition and αPD1 will (a) reduce mMDSCs infiltration and increase T cell infiltration and effector function and (b) alleviate edema and provide durable responses in GBMs that are refractory to WNT974+αPD1. If successful, our results will inform the design of future GBM clinical trials to improve the outcome of ICBs using agents current...