PROJECT SUMMARY/ABSTRACT Glioblastoma is one of the most aggressive and hard to treat human cancers facing modern medicine. The current standard of care for a new diagnosis of glioblastoma consists of surgical resection followed by a six and half weeklong course of concomitant chemo-radiation and another six-month-long course of adjuvant chemotherapy. Despite this aggressive and grueling treatment regimen, the majority of patients will suffer from tumor recurrence and nearly 90% will pass away within 5 years of initial diagnosis. These dismal survival rates indicate that glioblastoma possess mechanisms to resist current treatments. In recent years, the tumor microenvironment has increasingly been recognized for the essential role it plays in supporting cancer cells. Macrophages play a particularly important role in the tumor microenvironment both in terms of volume and function. These cells impact multiple aspects of the tumor microenvironment including suppressing anti-tumor immunity and controlling iron metabolism within the tumor niche. Iron is an essential nutrient required by cancer cells to fuel their proliferation. Without iron, cancer cells cannot proliferate. It is currently unknown how treatment with radiation and chemotherapy impact iron metabolism within macrophages and other infiltrating immune cells within the tumor microenvironment of glioblastoma. Aim 1 of this project will elucidate how iron metabolism is altered as a result of radiation and chemotherapy and will correlate these alterations to changes in anti-tumor immunity. Aim 2 of this project will study how intravenously delivered iron compounds impact iron metabolism and immune function within macrophages and other key immune cells within the tumor microenvironment. Additionally, aim 2 will investigate how administration of IV iron alters the vasculature within the tumor microenvironment. Anemia is a common co-morbidity among cancer patients that is frequently corrected with intravenous iron. Despite this, little is known regarding the effects of IV iron on the above-mentioned important aspects of the tumor microenvironment. This project will deepen our understanding of how treatments with chemotherapy, radiation, and supporting intravenous iron impact tumors with the hopes of identifying iron-based mechanisms of treatment resistance. Importantly, advances in iron supplements, chelators, and gene therapies make iron-based mechanisms of treatment resistance promising clinical targets to improve our current standard of care for glioblastoma.