LAUSR

Description TAK-981, a first-in-class small-molecule SUMOylation inhibitor, activates type I interferon signaling to promote antitumor immune responses in mice. Stopping SUMOylation to improve immune responses SUMOylation, a reversible posttranslational modification, can suppress type I interferon responses, potentially affecting the response to cancer treatment. Here, Lightcap and colleagues studied the effects of TAK-981, a small-molecule SUMOylation inhibitor, on human and mouse immune cells, finding that the compound promoted the activation of dendritic cells and T cells. They then tested TAK-981 on syngeneic cancers in mice, showing that TAK-981 inhibited tumor growth and increased intratumoral T cells and natural killer cells. The combination of TAK-981 with immune checkpoint blockade further improved survival in these mice, suggesting that the combination treatment could be beneficial for the treatment of cancers in humans. SUMOylation, the covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to protein substrates, has been reported to suppress type I interferon (IFN1) responses. TAK-981, a selective small-molecule inhibitor of SUMOylation, pharmacologically reactivates IFN1 signaling and immune responses against cancers. In vivo treatment of wild-type mice with TAK-981 up-regulated IFN1 gene expression in blood cells and splenocytes. Ex vivo treatment of mouse and human dendritic cells promoted their IFN1-dependent activation, and vaccination studies in mice demonstrated stimulation of antigen cross-presentation and T cell priming in vivo. TAK-981 also directly stimulated T cell activation, driving enhanced T cell sensitivity and response to antigen ex vivo. Consistent with these observations, TAK-981 inhibited growth of syngeneic A20 and MC38 tumors in mice, dependent upon IFN1 signaling and CD8+ T cells, and associated with increased intratumoral T and natural killer cell number and activation. Combination of TAK-981 with anti-PD1 or anti-CTLA4 antibodies improved the survival of mice bearing syngeneic CT26 and MC38 tumors. In conclusion, TAK-981 is a first-in-class SUMOylation inhibitor that promotes antitumor immune responses through activation of IFN1 signaling. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with solid tumors and lymphomas.