Purpose of review In the article, we focus on the role of SUMOylation in tumorigenesis and cancer-related processes, including Epithelial–mesenchymal transition (EMT), metastasis, resistance to cancer therapies, and antitumor immunity. Clinical perspective on small ubiquitin-like modifier (SUMO) inhibitors will be discussed. Recent findings SUMOylation regulates multiple important biologic functions including gene transcription, DNA damage repair, cell cycle, and innate immunity. The SUMO pathway enzymes are usually elevated in various cancers and linked with cancer progression and poor clinical outcomes for patients. Recent studies have revealed the role of SUMOylation in EMT and metastasis through regulating E-Cadherin and Snail expression. Multiple studies demonstrate SUMOylation is involved with chemoresistance and hormone treatment resistance. Oncogene Myc and SUMOylation machinery regulation has been revealed in pancreatic cancer. SUMOylation is involved in regulating antitumor immune response through dendritic cells and T cells. A breakthrough has been made in targeting SUMOylation in cancer as first-in-class SUMO E1 inhibitor TAK-981 enters clinical trials. Summary SUMOylation plays an important role in tumor EMT, metastasis, therapy resistance, and antitumor immune response. Pharmaceutical inhibition of SUMOylation has become promising clinical therapy to improve the outcome of the existing chemo and immune therapies.