Project Summary Glioblastoma is the most lethal form of primary brain cancer in adults with a median survival of approximately 14-16 months following diagnosis. In contrast to glioma cells, components of the tumor microenvironment (TME) of glioblastoma are genetically stable and are considering as the promising therapeutic targets. Tumor- associated macrophages (TAMs) are the most abundant cell population in the TME, which account for up to 50% of total cells in the entire glioblastoma tumor mass. Macrophages exhibit a spectrum of functions that span from an anti-tumor (known as M1) to a pro-tumor (known as M2) phenotype. TAMs are usually skewed toward a pro- tumor phenotype in glioblastoma. Given the predominance of these cells in glioblastoma, therapeutic strategies for their reprogramming to an anti-tumor phenotype is desirable. G protein-coupled receptors are a large family of receptors that are prominent pharmacological targets in biomedicine. Our preliminary data shows that G protein-coupled receptor 183 (GPR183) is highly expressed by TAMs in glioblastoma and may involve in TAM pro-tumor phenotype polarization. In this proposal, we will investigate whether and how GPR183 contributes to TAM pro-tumor phenotype polarization, reveal how such polarized TAMs promote tumor progression, and develop potential therapeutic strategies targeting TAM reprogramming in glioblastoma. To achieve these goals, we propose the following specific Aims: Aim 1. Clarify the role and underlying mechanism of GPR183 in TAM reprogramming in glioblastoma; Aim 2. Determine how GPR183-regulated TAM reprogramming promotes glioblastoma progression; and Aim 3. Basic to translational study: targeting TAM reprogramming using tumor samples and models from glioblastoma patients. We propose to employ integrated strategies combining gain- and loss-of-function approaches, in vitro and in vivo systems, as well as proteomic and transcriptomic analysis to test each Aim. Together, this project will uncover novel mechanisms for TAM reprogramming and reveal new immunotherapeutic strategies for glioblastoma.