ABSTRACT Colon cancer is the second leading cause of cancer deaths in the United States. Inflammation is an essential component of colon cancer initiation and progression. Most notable examples for such inflammatory conditions and subsequent tumors include colitis-associated colon cancer, where chronic pre-existing inflammation increases the risk of cancer. However, even sporadic colon cancers that are not linked to pre-existing inflammatory disease, inflammation can impact growth and progression. Our works also has carefully demonstrated that the recruitment of neutrophils is a critical mechanism by which HIF2α promotes colon cancer growth. We recently have found that gut microbiota metabolites are essential regulators of HIF2α expression and activity. However, it is unclear the role of the microbial metabolites in HIF2α regulation in colon cancer, does hypoxia have a cell autonomous role in the regulation of neutrophils, and can HIF2α be targeted in colon cancer? This research area is underexplored and has the potential to generate novel therapies and therapeutic targeted in colon cancer. The overall objective of this research proposal is to define the mechanistic underpinnings by which HIF2α via cooperative metabolite crosstalk potentiate colon cancer progression. Based on our preliminary data, we hypothesize that HIF2α activation in epithelial cells and neutrophils promote an immunosuppressive environment is critical in intestinal regeneration following injury and colon cancer progression. Our recent work identified that gut microbiota metabolites as essentially regulators of HIF2α and Aim 1 will delineate if microbial metabolite axis is the major mechanism regulating HIF2α in inflammation and colon cancer. Using a novel reporter mouse, we identified that neutrophils express high levels of HIF2α and Aim 2 will understand if cell autonomous HIF2α regulation in neutrophils is critical for immunosuppressive metabolite production in inflammation and colon cancer. The first on-target HIF2α inhibitor is undergoing clinical trials for renal cancers and has demonstrated promising results. In Aim 3 we will determine if this inhibitor provides any benefit alone or in an adjuvant setting with immune checkpoint blockers in preclinical models of colon cancer. Accomplishing these Aims will (i) uncover mechanisms of HIF2α regulation (ii) define new metabolic pathways that alter neutrophil function, and (iii) highlight new pathways, genetic vulnerabilities and drug targets for colon cancer.