Abstract 4495: Inhibition of OTUD4/CD73 proteolytic axis by novel small molecule inhibitor ST80 reinvigorates tumor immune response

Despite the widespread utilization of immunotherapy, the poor clinical response by immune-suppressive tumors is an emerging challenge in the use of current immune checkpoint inhibitors. Recent research has revealed that CD73, or Ecto-5′-nucleotidase, is an enzyme overexpressed in many cancers, and works in concert with CD39 to produce immunosuppressive extracellular adenosine, subsequently inhibiting CD8+ T cell responses. Our multi-omics analysis identified CD73 and OTUD4, a deubiquitinase that stabilizes CD73 by counteracting its that counteracts its E3 ligase-mediated ubiquitination and degradation, as potential targets for enhancing anti-cancer immune responses. Using druggability and pharmacophore simulations, we developed ST80, a novel small molecule inhibitor that disrupts the OTUD4-CD73 interaction by binding to the hydrophobic OTUD4 binding site on CD73. Within in vitro models of triple-negative breast cancer, EGFR-mutant lung cancer, ovarian cancer, and colorectal cancer, ST80 demonstrates significant potential in overcoming immune evasion by reducing adenosine production in the tumor microenvironment, subsequently reinvigorating the tumor immune responses by enhancing CD8+ T cell proliferation and IFN-γ production. By targeting the CD73/OTUD4 proteolytic axis, ST80 presents a promising strategy for treating cancers with immune-suppressive properties, potentially enhancing the efficacy of current immunotherapies. Citation Format: Kevin Li, Yueming Zhu, Yong Wan. Inhibition of OTUD4/CD73 proteolytic axis by novel small molecule inhibitor ST80 reinvigorates tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4495.