GUCY2C is a membrane-bound guanylate cyclase that catalyzes synthesis of cyclic GMP (cGMP) from GTP, functioning as a receptor for endogenous peptides guanylin and uroguanylin. This enzyme regulates intestinal fluid secretion and epithelial homeostasis in normal intestinal tissues. In gastrointestinal cancers, GUCY2C has emerged as a promising immunotherapeutic target because it is expressed nearly universally in colorectal cancers while remaining restricted to intestinal epithelial cells in normal tissue 1. Loss of GUCY2C signaling early in colorectal tumorigenesis suggests a tumor-suppressive role 2. Beyond cancer, GUCY2C agonists address gastrointestinal symptoms: neuropod cell GUCY2C selectively regulates visceral pain through direct modulation of sensory neurons, with the FDA-approved agonist linaclotide ameliorating pain in chr12 constipation syndromes 3. Multiple GUCY2C-targeted therapeutics are in clinical development. T-cell engaging bispecific antibodies such as PF-07062119 and CAR-T cell therapies demonstrate efficacy in colorectal cancer; in a phase 1 trial of dual CD19/GCC CAR-T cells in heavily pretreated metastatic colorectal cancer, the objective response rate was 40% with median overall survival of 22.8 months 4. FDA-approved GUCY2C agonists linaclotide and plecanatide address both constipation and visceral pain, while strategies targeting GUCY2C for cancer prevention remain under investigation 5.