ABSTRACT Leveraging neuroinflammation to improve treatment outcomes for patients with glioblastoma is challenging because the hypoxic tumor immune microenvironment (TIME), mostly comprised of immuno-suppressive tumor-associated macrophages (TAMs), remains incompletely quantified and therapeutically modulated. The long-term goal is to accelerate the development of clinically meaningful imaging technologies as a way to advance therapeutic approaches for patients with deadly brain malignancies. The overall objective in this application is to use novel iron nanoparticle enhanced 18F-fluoromisonidazole PET/MRI derived Segregation and Extravascular Localization of Ferumoxytol Imaging (SELFI) hypoxic fraction to quantitatively determine how hypoxia and TAM based neuroinflammation relate to treatment sensitivity. The central hypothesis is that therapeutic modulation of TAMs, as monitored by SELFI Hypoxic Fraction, ameliorates hypoxic TIME immunosuppression leading to improved treatment outcomes. The rationale for the proposed research is that quantitative elucidation of how the hypoxic TIME relates to treatment outcomes is likely to provide a strong scientific framework whereby new TAM based therapeutic strategies can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) Define a biologically specific imaging measure of the immuno- suppressive hypoxic TIME; and 2) Determine the effect of TAM modulators on the TIME of glioblastoma. Under the first aim, SELFI hypoxic fraction will be optimized and biologically validated in a cohort of 27 patients with IDH wild type glioblastoma needing surgical intervention for the diagnosis of treatment outcome. Additionally, the diagnostic and prognostic performance will be determined through longitudinal assessment of the hypoxic TIME in a prospective phase II clinical trial of 50 adult patients with newly diagnosed IDH wild type glioblastoma scheduled for standard therapy. For the second aim, syngeneic and