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<p>Our prior research identified MO-IPS as a potent MYC-PRMT inhibitor. Here, we re-evaluated its efficacy at optimized lower doses to explore a wider therapeutic window. MO-IPS retained robust anti-proliferative activity in vitro at reduced exposures. In MV-4-11 xenografts, the higher established dose suppressed tumor growth by 72.3% and enabled metabolomic profiling. This revealed a sequential mechanism: rapid MYC suppression followed by delayed downregulation of metabolic enzymes, inducing concurrent disruption of heme biosynthesis and NAD⁺ metabolism. Molecular docking predicted potential binding to UPP1, GAMT, and IDO2, and we observed that MO-IPS downregulates their expression at mRNA and protein levels. Critically, in an immunocompetent C1498 model, a lower, therapeutically relevant dose of MO-IPS (20&#xa0;mg/kg), titrated to minimize direct cytotoxicity, synergized with PD-1 therapy achieving 68.1% tumor inhibition. Mechanistically, the combination enhanced CD8⁺ T cell infiltration and reduced Treg accumulation, leading to an elevated CD8/Foxp3 ratio. This pivotal finding demonstrates that at reduced exposure, MO-IPS’s anti-leukemic efficacy is driven not by overt cytotoxicity but by metabolic reprogramming that establishes a pro-immunogenic tumor microenvironment. Collectively, our work repositions MO-IPS from a cytotoxic MYC-PRMT inhibitor to a multifaceted immunometabolic therapeutic. At optimized lower doses, it orchestrates a coordinated disruption of cancer metabolic vulnerabilities and actively augments anti-tumor immunity, presenting a refined and highly promising combinatorial strategy for AML.</p> Graphical Abstract <p></p>

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MO-IPS suppresses acute myeloid leukemia through metabolic reprogramming and synergizes with anti-PD-1 immunotherapy

  • 期刊论文

  • 发表日期：

    2026年6月17日

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  • Yingwen Wang,
  • Wenjun Zhao,
  • Yanrui Jin,
  • Chen Hu,
  • Xingqi Fang,
  • Shuhong Dong,
  • Baolai Zhang

摘要

Our prior research identified MO-IPS as a potent MYC-PRMT inhibitor. Here, we re-evaluated its efficacy at optimized lower doses to explore a wider therapeutic window. MO-IPS retained robust anti-proliferative activity in vitro at reduced exposures. In MV-4-11 xenografts, the higher established dose suppressed tumor growth by 72.3% and enabled metabolomic profiling. This revealed a sequential mechanism: rapid MYC suppression followed by delayed downregulation of metabolic enzymes, inducing concurrent disruption of heme biosynthesis and NAD⁺ metabolism. Molecular docking predicted potential binding to UPP1, GAMT, and IDO2, and we observed that MO-IPS downregulates their expression at mRNA and protein levels. Critically, in an immunocompetent C1498 model, a lower, therapeutically relevant dose of MO-IPS (20 mg/kg), titrated to minimize direct cytotoxicity, synergized with PD-1 therapy achieving 68.1% tumor inhibition. Mechanistically, the combination enhanced CD8⁺ T cell infiltration and reduced Treg accumulation, leading to an elevated CD8/Foxp3 ratio. This pivotal finding demonstrates that at reduced exposure, MO-IPS’s anti-leukemic efficacy is driven not by overt cytotoxicity but by metabolic reprogramming that establishes a pro-immunogenic tumor microenvironment. Collectively, our work repositions MO-IPS from a cytotoxic MYC-PRMT inhibitor to a multifaceted immunometabolic therapeutic. At optimized lower doses, it orchestrates a coordinated disruption of cancer metabolic vulnerabilities and actively augments anti-tumor immunity, presenting a refined and highly promising combinatorial strategy for AML.

Graphical Abstract