[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-353250-105":59,"doc-detail-353250-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","ptpn2-inhibition-unleashes-response-to-sting-agonism-in-head-and-neck-squamous-cell-cancer","PTPN2 inhibition unleashes response to STING agonism in head and neck squamous cell cancer","","cGAS-STING signaling regulates innate antitumor immunity, yet tumor-cell STING is suppressed in cancer subtypes that resist immune checkpoint blockade. STING agonists have often failed clinically, and targeted strategies to restore tumor-cell STING expression remain insufficiently explored. This study reports a head and neck squamous cell cancer mechanism of STING suppression via upregulation of PTPN2. Inhibition of PTPN2 restores IFNγ-STAT1–driven STING mRNA induction, increasing sensitivity to STING agonism and activating natural killer cells to suppress tumor growth in immune-cell-dependent anti-PD-1 refractory models.",{"@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":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/ptpn2-inhibition-unleashes-response-to-sting-agonism-in-head-and-neck-squamous-cell-cancer/353250/",{"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/ptpn2-inhibition-unleashes-response-to-sting-agonism-in-head-and-neck-squamous-cell-cancer/353250.png","ImageObject",300,407,{"name":92,"@type":93},"Anna Hans","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does the study address about STING agonists in cancer treatment?","Question",{"text":112,"@type":113},"STING agonists have failed in clinical trials, partly because tumor-cell STING expression is commonly suppressed in cancers that resist immune checkpoint blockade.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does PTPN2 inhibition affect STING expression in head and neck squamous cell cancer cells?",{"text":117,"@type":113},"PTPN2 inhibition increases tumor-cell STING by restoring IFNγ-STAT1–mediated induction of STING mRNA.",{"name":119,"@type":110,"acceptedAnswer":120},"What therapeutic outcomes result from restoring tumor-cell STING in anti-PD-1 refractory HNSCC models?",{"text":121,"@type":113},"Restored STING sensitivity promotes natural killer cell activation and suppresses tumor growth in an immune cell-dependent manner.","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},353250,1790175811,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"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},5909892332657,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","Article [https://doi.org/10.1038/s41467-026-72372-1](https://doi.org/10.1038/s41467-026-72372-1)  \nPTPN2 inhibition unleashes response to STING agonism in head and neck squamous cell cancer  \nReceived: 21 January 2025  \n\n| Accepted: 15 April 2026 |\n| --- |\n| |\n| Check for updates |\n\nZehua Li 1, Cong Fu1, Kartik Sehgal 1,2, Ann Marie Egloff1,2,3, Tran C. Thai1, Omar Avila Monge4,5, Cun Lan Chuong4,5, Yaiza Senent4,5, Maia Shea Lineberry6, Benjamin K. Eschle6, Koji Haratani 1, Elena V. Ivanova1,6, Marco Campisi 1, Navin R. Mahadevan1,7,8, John D. Quadarella 1, Patrick C. Gedeon 1,3, Jonathan D. Schoenfeld 1, Michihisa Kono 1, Caroline G. Fahey 1, Chayapatou Chayawatto6, Kenneth Ngo 6, Cloud P. Paweletz 1,6,  \nPrafulla C. Gokhale 6, Robert T. Manguso 4,5 , Ravindra Uppaluri 1,2,3,11  & David A. Barbie1,2,6,9,10,11   \ncGAS-STING signaling can promote antitumor immunity, and tumor cell STING is suppressed in a variety of cancer subtypes that resist immune checkpoint blockade. Although STING agonists have failed clinical trials, precision approaches targeting restoration of tumor cell STING expression have yet tobe explored. Here, we report that head and neck squamous cell cancer (HNSCC) exhibits a mechanism of STING suppression related to upregulation of protein tyrosine phosphatase non-receptor (PTPN) type 2 (PTPN2) that is also evident in other cancers. PTPN2 inhibition (PTPN2i) increases HNSCC tumor cell STING by restoring IFNγ-STAT1–mediated induction of STING mRNA. This restores sensitivity to STING agonism and natural killer cell activation, suppressing tumor growth in an immune cell-dependent manner in anti-PD-1 refractory syngeneic HNSCC mouse tumor models in female mice. Together, these findings demonstrate that PTPN2i can unleash STING agonist response, providing a rationale for the evaluation of this therapeutic combination in HNSCC and potentially other cancer types.  \nThe cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway has emerged as a key regulator of innate immunity across multiple types of cancers1,2. cGAS recognizes cytosolic double-stranded DNA derived from microbial pathogens or aberrantly released self-DNA, and then catalyzes the production of the  \nsecond messenger 2′3′-cyclic GMP-AMP (2′3′-cGAMP)3. 2′3′-cGAMP binds and activates STING, which subsequently activates TANKbinding kinase 1 (TBK1) to phosphorylate IRF3 (p-IRF3), resulting in the production of type I interferons, proinflammatory cytokines, and chemokines2. Pharmacologic activation ofthe cGAS-STING pathway by  \n1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 2Harvard Medical School, Boston, MA, USA. 3Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA. 4Broad Institute of MIT and Harvard, Cambridge, MA, USA. 5Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. 6Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. 7Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA. 8Department of Pathology, University of Michigan, Ann Arbor, MI, USA. 9Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 10Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA, USA. 11These authors jointly supervised this work: Ravindra Uppaluri, David A. Barbie e-mail: [rmanguso@broadinstitute.org](rmanguso@broadinstitute.org); [ravindra_uppaluri@dfci.harvard.edu](ravindra_uppaluri@dfci.harvard.edu); [david_barbie@dfci.harvard.edu](david_barbie@dfci.harvard.edu)  \nnatural STING ligand cyclic di-nucleotides (CDNs), or synthetic STING agonists such asADU-S100(ADU), can promote antitumor immunity in the syngeneic mouse models, including head and neck squamous cell carcinoma (HNSCC)4,5. However, STING agonists have yet to achieve success in clinical trials, even when combined with anti-PD-1 therapy6,7. Potential underlying mechanisms for ","cbCaitnDUVZCVoYJ","https://ap.wps.com/l/cbCaitnDUVZCVoYJ","pdf",3524100,17,"English","# Background\n## cGAS-STING pathway and STING agonists\n## Clinical limitations and proposed mechanisms\n# Key Findings\n## PTPN2-driven suppression of tumor-cell STING\n## Restoration of IFNγ-STAT1–mediated STING induction\n## Effects on NK activation and tumor growth\n# Implications\n## Therapeutic rationale for PTPN2i with STING agonists","[{\"question\":\"What problem does the study address about STING agonists in cancer treatment?\",\"answer\":\"STING agonists have failed in clinical trials, partly because tumor-cell STING expression is commonly suppressed in cancers that resist immune checkpoint blockade.\"},{\"question\":\"How does PTPN2 inhibition affect STING expression in head and neck squamous cell cancer cells?\",\"answer\":\"PTPN2 inhibition increases tumor-cell STING by restoring IFNγ-STAT1–mediated induction of STING mRNA.\"},{\"question\":\"What therapeutic outcomes result from restoring tumor-cell STING in anti-PD-1 refractory HNSCC models?\",\"answer\":\"Restored STING sensitivity promotes natural killer cell activation and suppresses tumor growth in an immune cell-dependent manner.\"}]","PTPN2 inhibition unleashes response to STING agonism in head and neck squamous cell cancer | PDF",1790103865,43]