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Mechanistically, OTUD4 deubiquitylates CD73, counteracting TRIM21-mediated ubiquitylation to stabilize CD73 and inhibit tumor immune responses. TGF-β signaling organizes this axis in tumor cells. Spatial transcriptomics resolves interacting malignant and immune cell features involving OTUD4 and CD73 expression, and the inhibitor ST80 disrupts their proteolytic interaction, restoring cytotoxic CD8+ T cell activity. In preclinical TNBC models, ST80 sensitizes refractory tumors to anti-PD-L1 therapy.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/pharmacological-suppression-of-the-otud4cd73-proteolytic-axis-revives-antitumor-immunity-against-immune-suppressive-breast-cancers-research-article/330644/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/pharmacological-suppression-of-the-otud4cd73-proteolytic-axis-revives-antitumor-immunity-against-immune-suppressive-breast-cancers-research-article/330644.png","ImageObject",300,407,{"name":42,"@type":43},"Eliana","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-27","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",11,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why are immune-suppressive (immune-cold) tumors challenging for current immunotherapy?","Question",{"text":63,"@type":64},"Immune-cold tumors show poor clinical responses because they have immunosuppressive properties and limited immunogenicity, including reduced T lymphocyte infiltration. This constrains the broad effectiveness of current immune checkpoint inhibitors.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What role does the OTUD4/CD73 proteolytic axis play in TNBC?",{"text":68,"@type":64},"OTUD4 counteracts TRIM21-mediated ubiquitylation of CD73 by deubiquitylating it, which stabilizes CD73 and suppresses tumor immune responses. The axis is further orchestrated by TGF-β signaling within tumor cells.",{"name":70,"@type":61,"acceptedAnswer":71},"How does the inhibitor ST80 affect tumor-immune interactions and therapy response?",{"text":72,"@type":64},"ST80 specifically disrupts the proteolytic interaction between CD73 and OTUD4, reinvigorating cytotoxic CD8+ T cell activity. 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Ivanov,1,2,5 Amad Uddin,1 Qiao Jiao,1 Junlong Jack Chi,1,6 Lidan Zeng,1 Ji Young Lee,3 Yifan Xue,7 Xinghua Lu,7 Massimo Cristofanilli,8 William J. Gradishar,4 Curtis J. Henry,2,9 Theresa W. Gillespie,2,10,11 Manali Ajay Bhave,2,11 Kevin Kalinsky,2,11 Haian Fu,1,2,5 Ivet Bahar,3,12 Bin Zhang,4 and Yong Wan1,2,11  \n1Department of Pharmacology and Chemical Biology and 2Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA. 3Laufer Center for Physical and Quantitative Biology, School of Medicine, Stony Brook University, Stony Brook, New York, USA. 4Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 5Emory Chemical Biology Discovery Center, Emory University School of Medicine, Emory University, Atlanta, Georgia, USA. 6Driskill Graduate Program (DPG), Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 7Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. 8Department of Medicine, Weill Cornell Medicine, New York, New York, USA. 9Department of Pediatrics, 10Department of Surgery, and 11Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA. 12Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, New York, USA.  \nDespite widespread utilization of immunotherapy, treating immune-cold tumors remains a challenge. Multiomic analyses and experimental validation identified the OTUD4/CD73 proteolytic axis as a promising target in treating immune-suppressive triple negative breast cancer (TNBC). Mechanistically, deubiquitylation of CD73 by OTUD4 counteracted its ubiquitylation by TRIM21, resulting in CD73 stabilization inhibiting tumor immune responses. We further demonstrated the importance of TGF-β signaling for orchestrating the OTUD4/CD73 proteolytic axis within tumor cells. Spatial transcriptomics profiling discovered spatially resolved features of interacting malignant and immune cells pertaining to expression levels of OTUD4 and CD73. In addition, ST80, a newly developed inhibitor, specifically disrupted proteolytic interaction between CD73 and OTUD4, leading to reinvigoration of cytotoxic CD8+ T cell activities. In preclinical models of TNBC, ST80 treatment sensitized refractory tumors to anti-PD-L1 therapy. Collectively, our findings uncover what we believe to be a novel strategy for targeting the immunosuppressive OTUD4/CD73 proteolytic axis in treating immune-suppressive breast cancers with the inhibitor ST80 .  \nIntroduction  \nDespite the widespread utilization of immunotherapy, the poor clinical response by immune-suppressive tumors is an emerging challengein use of current immune checkpoint inhibitors. Triple negative breast cancers (TNBCs) are the most aggressive mammary carcinoma subtype and have few effective targeted therapies. Although PD-L1 inhibitors demonstrated their promising clinical benefits in certain subsets of patients with TNBC, the intricacies of the tumor microenvironment, with its inherent immunosuppressive properties and varied immunogenicity profiles, limit the broad efficacy of such therapies (1–3). Breast cancer’s “immune-cold” property caused by a scarcity of T lymphocyte infiltration and expression of different  \nRelated Commentary: [https://doi.org/10.1172/JCI180914](https://doi.org/10.1172/JCI180914)  \nAuthorship note: YZ, AB, and PX are cofirst authors. IB, BZ, and YW are cocorresponding authors.  \nConflict of interest: PPI inhibitors for OTUD4/CD73 are under process of patent application under patent application number 63/585,613 . The inventors listed o","cbCaitEE7w9uGpw3","https://ap.wps.com/l/cbCaitEE7w9uGpw3","pdf",5978752,"English","# Introduction\n## Immunotherapy challenge in immune-suppressive tumors\n## Rationale for targeting OTUD4/CD73 in TNBC\n## Role of CD73 in immunosuppressive adenosine signaling","[{\"question\":\"Why are immune-suppressive (immune-cold) tumors challenging for current immunotherapy?\",\"answer\":\"Immune-cold tumors show poor clinical responses because they have immunosuppressive properties and limited immunogenicity, including reduced T lymphocyte infiltration. This constrains the broad effectiveness of current immune checkpoint inhibitors.\"},{\"question\":\"What role does the OTUD4/CD73 proteolytic axis play in TNBC?\",\"answer\":\"OTUD4 counteracts TRIM21-mediated ubiquitylation of CD73 by deubiquitylating it, which stabilizes CD73 and suppresses tumor immune responses. The axis is further orchestrated by TGF-β signaling within tumor cells.\"},{\"question\":\"How does the inhibitor ST80 affect tumor-immune interactions and therapy response?\",\"answer\":\"ST80 specifically disrupts the proteolytic interaction between CD73 and OTUD4, reinvigorating cytotoxic CD8+ T cell activity. In preclinical TNBC models, ST80 treatment sensitizes refractory tumors to anti-PD-L1 therapy.\"}]","Pharmacological suppression of the OTUD4/CD73 proteolytic axis revives antitumor immunity against immune-suppressive breast cancers - Research article | PDF",1789989626,48]