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Reduced MHC-I antigen presentation is a key resistance mechanism. The study shows that UHRF1, an epigenetic regulator, displays altered expression and aberrant cytosolic localization in tumors, where it promotes MHC-I ubiquitination and degradation. Tumor microenvironment signals, including TGF-β, trigger UHRF1 phosphorylation-dependent cytoplasmic translocation that enables MHC-I binding, suppressing antigen presentation and shaping an immune-hostile milieu.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/aberrant-cytoplasmic-expression-of-uhrf1-restrains-the-mhc-i-mediated-anti-tumor-immune-response-research-article-summary/331356/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/aberrant-cytoplasmic-expression-of-uhrf1-restrains-the-mhc-i-mediated-anti-tumor-immune-response-research-article-summary/331356.png","ImageObject",300,407,{"name":92,"@type":93},"Riley","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does UHRF1 affect MHC-I in tumors?","Question",{"text":112,"@type":113},"UHRF1 shows altered expression and aberrant cytosolic localization in cancer tissues and promotes MHC-I ubiquitination and degradation, which reduces antigen presentation.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What triggers UHRF1 cytoplasmic translocation?",{"text":117,"@type":113},"Cytoplasmic translocation of UHRF1 is induced by phosphorylation on a specific serine in response to signals from the tumor microenvironment, such as TGF-β.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the therapeutic impact of inactivating UHRF1?",{"text":121,"@type":113},"Genetic deletion of UHRF1 synergizes with immune checkpoint blockade and induces an anti-tumor memory response by evoking low-affinity T cells.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},331356,1790194461,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":29,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},1374391975076,"https://ap-avatar.wpscdn.com/avatar/14000253ca4ec9f6853?x-image-process=image/resize,m_fixed,w_180,h_180&k=1783305029341752051","Article [https://doi.org/10.1038/s41467-024-52902-5](https://doi.org/10.1038/s41467-024-52902-5)  \nAberrant cytoplasmic expression ofUHRF1 restrains the MHC-I-mediated anti-tumor immune response  \nReceived: 26 March 2024  \n\n| Accepted: 24 September 2024 |\n| --- |\n| |\n| Check for updates |\n\nLianmei Tan 1,8, Tao Yin1,2,8, Handan Xiang 1,8, Liuyang Wang3,  \nPoorva Mudgal4, Junying Chen1, Yi Ding1, Guoping Wang2, Bryan Jian Wei Lim 2, Yuqi Huang 5, De Huang1, Yaosi Liang 1, Peter B. Alexander1, Kun Xiang 1, Ergang Wang 1, Chengsong Yan1, Zhehao Ma1, Minjia Tan 5,  \nQi-Jing Li 2,6,7  & Xiao-Fan Wang 1   \nImmunotherapy successfully complements traditional cancer treatment. However, primary and acquired resistance might limit efficacy. Reduced antigen presentation by MHC-I has been identified as potential resistance factor. Here we show that the epigenetic regulator ubiquitin-like with PHD and ring finger domains 1 (UHRF1), exhibits altered expression and aberrant cytosolic localization in cancerous tissues, where it promotes MHC-I ubiquitination and degradation. Cytoplasmic translocation of UHRF1 is induced by its phosphorylation on a specific serine in response to signals provided by factors present in the tumor microenvironment (TME), such as TGF-β, enabling UHRF1 to bind MHC-I. Downregulation of MHC-I results in suppression of the antigen presentation pathway to establish an immune hostile TME. UHRF1 inactivation by genetic deletion synergizes with immune checkpoint blockade (ICB) treatment and induces an anti-tumour memory response by evoking low-affinity T cells. Our study adds to the understanding of UHRF1 in cancer immune evasion and provides a potential target to synergize with immunotherapy and overcome immunotherapeutic resistance.  \nIn recent years, immunotherapy has significantly improved the prognosis of patients with certain types of cancer1,2. The anti-cancer immunity process initiates with the priming and activation of immune cells by antigen-presentation cells. Upon recirculate into the tumor, the activated immune cells recognize cognate antigens presented on MHC molecules of tumor cells, leading to tumor cell destruction3. However, a majority of patients develop primary and acquired resistance to immunotherapy, with only a subgroup experiencing longterm benefits4. Resistance is a multifactorial process; as a part of  \ncancer-immune co-evolution, cancer cells develop multiple intrinsic and extrinsic mechanisms to evade anti-cancer immunity5. For instance, impaired MHC-I antigen processing leads to acquired resistance to immune checkpoint blockade (ICB) treatment6. However, the complex molecular mechanisms whereby cancer cells restrain MHC-I remain to be further explored.  \nThe tumor microenvironment (TME) plays a critical role in cancer development and progression7. Aberrant features frequently observed in the TME include hypoxia, abnormal vasculature, and altered  \n1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. 2Department of Immunology, Duke University School of Medicine, Durham, NC, USA. 3Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA. 4TCRCure Biopharma, Durham, NC, USA. 5State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. 6Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. 7Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. 8These authors contributed equally: Lianmei Tan, Tao Yin, Handan Xiang. e-mail: [Li_QiJing@imcb.a-star.edu.sg](Li_QiJing@imcb.a-star.edu.sg); [xiao.fan.wang@duke.edu](xiao.fan.wang@duke.edu)  \nmetabolism8–10. Notably, dynamic intercellular communications occur within the TME7, resulting in biochemical cues that influence behaviors of both tumor and immune cells. Moreover, through the activ","cbCairgha09pNCtz","https://ap.wps.com/l/cbCairgha09pNCtz","pdf",3084224,15,"English","# Overview\n## Background: immunotherapy resistance and MHC-I\n## Tumor microenvironment and immune suppression\n# UHRF1 mechanism and consequences\n## Cytoplasmic translocation and MHC-I degradation\n## Impact on antigen presentation and immune cold TME\n# Therapeutic implications\n## UHRF1 inactivation and synergy with ICB\n## Inducing anti-tumor memory responses","[{\"question\":\"How does UHRF1 affect MHC-I in tumors?\",\"answer\":\"UHRF1 shows altered expression and aberrant cytosolic localization in cancer tissues and promotes MHC-I ubiquitination and degradation, which reduces antigen presentation.\"},{\"question\":\"What triggers UHRF1 cytoplasmic translocation?\",\"answer\":\"Cytoplasmic translocation of UHRF1 is induced by phosphorylation on a specific serine in response to signals from the tumor microenvironment, such as TGF-β.\"},{\"question\":\"What is the therapeutic impact of inactivating UHRF1?\",\"answer\":\"Genetic deletion of UHRF1 synergizes with immune checkpoint blockade and induces an anti-tumor memory response by evoking low-affinity T cells.\"}]","Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response - Research article summary | PDF",1789992889,38]