SUMOylation is a critical post-translational modification that modulates protein activity, stability, and subcellular distribution through the covalent attachment of SUMO proteins (SUMO1-5) to specific targets. This process is mediated by a cascade of enzymes, including E1, E2, E3 ligases, and deSUMOylation enzymes, enabling precise control over diverse biological functions such as gene expression, cell cycle regulation, DNA damage repair, signaling cascades, and metabolic pathways. Dysregulation of SUMOylation enzymes has been contributes to cancer initiation, and treatment resistance, by enhancing tumor cell motility, aggressiveness, and epithelial-mesenchymal transition (EMT). In gastrointestinal malignancies-including gastric, hepatic, colorectal, esophageal, gallbladder, and pancreatic cancers-SUMOylation drives tumor growth, metastasis, and invasiveness by reprogramming metabolic processes, signaling networks, and the surrounding tumor niche. Additionally, it contributes to resistance against chemotherapy and radiotherapy. Understanding the molecular basis of SUMOylation not only underscores its significance in oncogenesis but also provides a foundation for developing novel anticancer therapies.