The SUMOylation inhibitor TAK-981 (Subasumstat) triggers IFN-I-dependent activation of Natural Killer cells against Acute Myeloid Leukemias

Natural Killer (NK) cells play a pivotal role in mounting an anti-cancer immune response. Patients with diminished NK cells number and activity face less favorable prognosis. Promising therapeutic strategies include the adoptive transfer of NK cells or the reactivation of patients’ own NK cells. TAK-981, a first-in-class inhibitor of SUMOylation undergoing phase I/II clinical trials for cancer, is emerging as an immunomodulatory drug. Here, we demonstrate that TAK-981 activates NK cells from healthy donors and patients with Acute Myeloid Leukemia (AML), a cancer with very poor prognosis. TAK-981 heightens their degranulation capacity, secretion of inflammatory cytokines (IFN-γ, TNF-α, FasL), and cytotoxicity against AML cells. In vivo , TAK-981 also enhances the anti-leukemic activity of ex-vivo expanded human NK cells. At the molecular level, TAK-981 first induces IFNB1 gene in NK cells, leading to the secretion of type I Interferon (IFN-I), which binds to the Interferon receptor IFNAR. This induces Interferon-Stimulated Genes (ISG) and activates NK cells in vitro and in vivo . Finally, TAK-981 stimulates IFN-I secretion by monocytes, which contributes to the activation of NK cells in trans . Altogether, targeting SUMOylation could be a promising strategy to reactivate AML patients’ NK cells and enhance the efficiency of NK cells-based therapies.