GUCY2C-targeting approaches. GUCY2C is an intestinal mucosal receptor involved in epithelial homeostasis and tumor suppression. Loss of GUCY2C ligands, silencing GUCY2C signaling, is an early step in tumorigenesis, leading to oncogenic signaling, metabolic reprogramming, loss of epithelial barrier integrity, and cell proliferation. Oral replacement of lost ligands is a strategy to prevent colorectal cancer. Furthermore, colorectal cancer cells overexpress GUCY2C, providing a target for immunotoxin therapy or T cell-mediated immunotherapies to eliminate metastases. Imaging agents also can target GUCY2C, improving disease detection and the monitoring of treatment progress.