SUMOylation, as a key post-translational modification mechanism, precisely regulates protein function, stability and subcellular localization by covalently linking SUMO proteins to substrates, and plays a central role in cellular signaling, transcriptional regulation, and maintenance of genomic stability (Sheng Et Al., 2025). Recent studies have shown that the SUMOylation pathway plays a dual role in the development of digestive tract tumors (including gastric, hepatocellular, and colorectal cancers, etc.): on the one hand, it directly promotes tumor progression by reprogramming tumor cell metabolism, driving epithelial-mesenchymal transition (EMT), and enhancing the ability of DNA damage repair (Zhou et al., 2024a); on the other hand, it indirectly supports the tumor microenvironment by reshaping the tumor microenvironment (e.g., modulating the immune cell polarization) immune escape (Zhao et al., 2024a; Tharuka et al., 2025; K et al., 2021). Notably, aberrant expression of SUMO chemoenzymes (e.g., UBC9, PIAS family) is significantly correlated with enhanced tumor aggressiveness and chemotherapy resistance, and has become a potential biomarker for assessing prognosis (Brackett and Blagg, 2021).

Currently, Gastrointestinal (GI) Tumors are facing serious challenges: (1) limitations of traditional therapies: surgical resection has limited efficacy in advanced patients, and radiotherapy is prone to treatment failure due to SUMO-mediated enhancement of DNA repair (e.g., Rad51 regulation) and apoptosis resistance (Wu et al., 2025a); (2) tumor heterogeneity: the specificity of SUMO-mediated substrates varies among different GI tumors, which adds to the complexity of targeted therapies (Tian et al., 2021; Zhao et al., 2024b; Liu et al., 2024; Cao et al., 2025); (3) microenvironmental barriers: SUMOylation-driven immunosuppressive microenvironments(e.g., M2-type macrophage polarization) weaken immunotherapeutic effects (Xiao et al., 2022). Interventional strategies targeting SUMOylation have demonstrated significant potential: preclinical studies have shown that SUMO E1 inhibitors (e.g., TAK-981) can block the SUMO cascade response, significantly inhibit GI tumor growth and reverse drug resistance by inducing tumor cell cycle arrest and enhancing immunogenicity (GU et al., 2023; kukkula et al., 2021). However, the functional specificity, substrate selectivity, and interactions with modifications such as ubiquitination of SUMO isoforms (SUMO1/2/3) still need to be deeply resolved, and these mechanistic gaps limit the clinical translation of targeted drugs (Shi et al., 2023; Wang and Matunis, 2023).

The aim of this review is to explore the role of SUMOylation in GI tumors and its potential therapeutic strategies, to analyze the challenges and limitations of current studies, and to propose directions and values for future research. By summarizing the existing literature, we hope to provide new perspectives and ideas for the study of GI tumors and promote the progress of related fields.