ABSTRACT An estimated 45,230 individuals were diagnosed with rectal cancer in the United States in 2021. Rectal cancer is primarily managed using a combination of chemotherapy, radiation, and surgery. Surgical resection of the rectum is associated with long-term functional deficits and decreased quality-of-life. Therefore, strategies to improve response to neoadjuvant chemoradiotherapy could increase non-surgical curative rates and enhance quality-of-life for rectal cancer patients. Carbon monoxide (CO) at low, non-toxic concentrations has been shown to provide paradoxical anti-tumor effects while inhibiting inflammation and oxidative-stress induced normal tissue injury that could serve as an adjuvant treatment to enhance chemo-radiotherapy efficacy. CO is a product of heme catabolism regulated by the Nrf2 transcription factor and the cytoprotective gene Heme Oxygenase-1 (HO- 1). The biochemical mechanisms by which CO simultaneously sensitizes tumor cells to die while preserving normal cell survival are unknown but likely involve fundamental differences in oxidative metabolism between cancer and normal cells. Identifying targetable redox sensitive mechanisms underlying the activity of CO in rectal cancer could rapidly lead to translational therapeutic approaches for improving radiation responses in cancers while limiting normal tissue injury. We have developed exciting new methods for CO delivery through the gastrointestinal (GI) tract to overcome the challenges of inhaled CO. Using these GI formulations to deliver CO, our central hypothesis is that CO, delivered as a safe biofoam, selectively chemo-radio-sensitizes rectal cancer while reducing normal tissue injury. Further that the mechanism involves differential effects on Nrf2/HO-1 signaling and modulation of mitochondrial oxidative metabolism. We will evaluate the impact of cytoprotective CO biofoams on normal rectal tissue responses and oxidative damage after exposure to chemoradiotherapy and determine the effects of CO as an adjunct to therapy for rectal cancer in mice.