The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is lower than 8%. PDAC has the characteristics of high-density stroma and a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemo and immunotherapy. SUMOylation is a reversible post-translational modification required for cell cycle progression. We found that SUMOylation is increased in PDAC patient samples compared to primary pancreatic tissue. TAK-981, a novel highly selective and potent small molecule inhibitor of the SUMO activation enzyme E1 (SAE), selectively decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. In vivo TAK-981 efficiently limited the tumor burden in the KPC3 syngeneic mouse model without evidence of general toxicity. Interestingly, we found that TAK-981 modulates the immune system, up-regulating CD8+ T cells, NK cells and down-regulating B cells in peripheral blood, spleen, lymph nodes. Treatment of mouse primary T cells ex vivo with TAK-981 activated STAT1, the key transcription factor induced by interferon signaling. Our findings indicate that inhibition of the SUMO pathway might be a potential clinical strategy to target PDAC by inhibiting tumor cell division and activating anti-tumor immunity.