Insights into SUMOylation in gastric cancer: molecular mechanisms and emerging therapeutic opportunities

Gastric cancer remains a significant global health challenge due to its aggressive behavior, high mortality rates, and limited treatment success. Growing research underscores the critical role of SUMOylation, a reversible post-translational modification, in regulating key cellular processes such as DNA repair, gene expression, genomic stability, and signaling pathways. Aberrant SUMOylation is closely linked to gastric cancer development, metastasis, and resistance to therapies, positioning it as a potential therapeutic target. This review consolidates current knowledge of the SUMOylation system, which involves activating (E1), conjugating (E2), and ligating (E3) enzymes, alongside SUMO-specific proteases (SENPs) that reverse the modification. We explore how SUMOylation influences cancer-promoting and tumor-suppressing pathways by stabilizing or degrading critical proteins, modulating immune responses, driving epithelial-mesenchymal transition, and contributing to chemoresistance. Furthermore, we discuss promising therapeutic approaches targeting SUMOylation, including small-molecule inhibitors, natural bioactive compounds, and synthetic lethal strategies that exploit SUMO pathway weaknesses. Preclinical studies suggest these approaches could enhance chemotherapy and immunotherapy effectiveness, offering new precision treatment options. Deepening our understanding of SUMOylation in gastric cancer is vital for developing innovative, mechanism-driven therapies to improve patient outcomes.