Therapeutic Synergy and Immune Activation by SUMOylation Pathway Inhibition in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically aggressive malignancy with poor outcomes driven by frequent relapse and therapeutic resistance. Because the SUMOylation pathway regulates genome maintenance, transcription control, and immune evasion, it represents a promising therapeutic target in AML. We evaluated the therapeutic and immunomodulatory effects of TAK-981 using patient-derived AML samples and preclinical models. Expression of SUMO pathway components (SAE1, SAE2, and UBC9) was assessed in newly diagnosed AML and correlated with bone marrow blast burden. Anti-leukemic activity and drug interactions with venetoclax and gilteritinib were tested in vitro and ex vivo and validated in xenograft models, while immune reprogramming was characterized in immunocompetent AML models by profiling immune subsets and effector cytokine/mediator signatures. SAE1, SAE2, and UBC9 were significantly higher in bulk diagnostic specimens than in remission specimens and positively correlated with blast percentages. TAK-981 showed potent anti-leukemic activity and synergized with venetoclax and gilteritinib in vitro and ex vivo. In xenograft studies, TAK-981 enhanced the efficacy of both agents, and a four-week triplet regimen produced durable disease control and superior survival benefit with a favorable safety profile. In immunocompetent models, TAK-981 induced systemic immune remodeling, including increased CD8⁺ T-cell and NK-cell frequencies, memory T-cell polarization, and sustained elevation of granzyme B, IFN-γ, and TNF-α. These findings support SUMO pathway inhibition with TAK-981 as a promising combinatorial strategy to improve treatment durability and overcome resistance in AML through both direct anti-leukemic effects and immune reprogramming.