SUMOylation regulates tumorigenesis and progression: Molecular mechanisms and therapeutic applications

Abstract SUMOylation is a dynamic and reversible post‐translational modification that has evolved from a regulator of fundamental cellular processes to a key driver of tumorigenesis and progression. By centering on three core pathological dimensions, namely aberrant cell death, metabolic reprogramming, and immune microenvironment dysfunction, this review systematically elucidates how SUMOylation orchestrates malignant tumor progression through these interconnected axes. It provides a detailed overview of the SUMOylation enzymatic cascade, its regulatory features including dynamics, substrate specificity, and responsiveness to cellular stress, and its complex crosstalk with other modifications such as ubiquitination and phosphorylation, which together enable precise and context‐dependent functional outcomes in various cancers. A distinctive aspect of this review is its integration of mechanistic insights with emerging therapeutic strategies, evaluating the translational potential of targeting the SUMO pathway, highlighting opportunities to overcome drug resistance and modulate antitumor immunity, while also addressing current challenges in clinical development. In contrast to most existing reviews that follow a trajectory from molecular mechanism to tumor type specific roles, this review presents a paradigm shift by organizing the regulatory network of SUMOylation in cancer around three pathological axes aberrant cell death, metabolic reprogramming, and immune dysfunction, a framework that aligns more closely with the core pathological drivers of tumor progression and transcends conventional classifications based on tumor type or individual signaling pathways. In parallel, the review emphasizes key nodes of crosstalk with ubiquitination and identifies translational bottlenecks, offering targeted insights for the development of personalized therapeutic strategies directed at the SUMO pathway while establishing a theoretical foundation for SUMOylation as a novel therapeutic axis in oncology.