[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-354313-105":59,"doc-detail-354313-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","metformin-enhances-trail-mediated-antitumor-activity-of-liver-natural-killer-cells-in-mice","Metformin enhances TRAIL-mediated antitumor activity of liver natural killer cells in mice","","Metformin’s anticancer effects have been linked to anti-inflammatory signaling and AMPK-mediated mTOR inhibition, yet its impact on intrahepatic immunity remains unclear. Prior work showed mTOR inhibition strengthens liver NK-cell antitumor activity by increasing TRAIL. This study tested whether metformin modulates TRAIL expression on liver NK cells, finding increased TRAIL+ liver NK subsets, enhanced cytotoxicity against TRAIL-sensitive targets, reduced tumor growth in vivo, and AMPK signaling involvement.",{"@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/metformin-enhances-trail-mediated-antitumor-activity-of-liver-natural-killer-cells-in-mice/354313/",{"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/metformin-enhances-trail-mediated-antitumor-activity-of-liver-natural-killer-cells-in-mice/354313.png","ImageObject",300,407,{"name":92,"@type":93},"Mimi","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does metformin influence liver natural killer (NK) cell antitumor activity?","Question",{"text":112,"@type":113},"Metformin increases the proportion of TRAIL+ liver NK cells, enhances NK-cell cytotoxicity against TRAIL-sensitive tumor targets, and suppresses tumor growth in vivo.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What mechanistic pathway may mediate metformin’s effects on TRAIL+ liver NK cells?",{"text":117,"@type":113},"The AMPK signaling axis is implicated in promoting the increase of TRAIL+ liver NK-cell subsets.",{"name":119,"@type":110,"acceptedAnswer":120},"What cell subsets are reported to expand after metformin treatment?",{"text":121,"@type":113},"Metformin increases a liver-resident NK-like (type 1 innate lymphoid cell, ILC1) Eomeslow, TRAILhigh subset.","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},354313,1790193342,{"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":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":31},2336477974920,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","[www. nature.com/scientificreports](www. nature.com/scientificreports)  \nOPEN  \nMetformin enhances TRAILmediated antitumor activity of liver natural killer cells in mice  \nTomoaki Bekki1, Masahiro Ohira1,2􀀍, Yuki Imaoka1, Kouki Imaoka1, Hiroaki Niitsu3, YukaTanaka1, Tsuyoshi Kobayashi1 & Hideki Ohdan1  \nMetformin exerts antitumor activity across multiple cancers, largely attributed to anti-inflammatory effects and the AMP-activated protein kinase (AMPK)-mediated inhibition of mammalian target of rapamycin (mTOR). However, the effects of metformin on intrahepatic immunity remain poorly defined. We previously demonstrated that mTOR inhibition augments the antitumor function of liver natural killer (NK) cells by upregulating tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) . Here, we investigated whether metformin modulates TRAIL expression on liver NK cells. Compared with vehicle control, metformin increased the proportion of TRAIL+ liver NK cells, enhanced the cytotoxicity of liver NK cells against TRAIL-sensitive tumor targets, and suppressed tumor growth in vivo. Mechanistically, metformin increased the proportion of liver-resident NK (also known as type 1 innate lymphoid cells)-like cells which are Eomeslow, TRAILhigh subset. Moreover, activation of the AMPK signaling axis may contribute to metformin-induced promotion of TRAIL+ liver NK cells. These findings indicate that metformin potentiates the antitumor activity of liver NK cells via increasing the proportion of TRAIL+ NK cells, supporting its potential repositioning as an immunomodulatoryadjuvant for liver cancer.  \nKeywords Eomes, Metformin, Liver-resident NK cells/ILC1, TRAIL  \nMetformin, used widely as the first-line treatment for type 2 diabetes mellitus, has garnered attention for its potential anticancer properties. Epidemiological studies have suggested that patients with diabetes receiving metformin exhibit a reduced incidence of various malignancies compared to those not on metformin therapy1,2. Improved postoperative outcomes and reduced recurrence rates have been reported in metformin-treated patients with cancer3–7. Similar trends have been observed in hepatocellular carcinoma (HCC), with evidence indicating that metformin reduces the risk of HCC development8,9 and enhances postoperative prognosis10, 11.  \nMetformin’s antitumor effects are mediated by direct action on tumor cells and by indirect immune response modulation. Among immune cells, natural killer (NK) cells, particularly those residing in the liver, are recognized for their robust cytotoxicity against HCC cells12, 13. NK cells, which are large granular cells classified as subset 1 innate lymphoid cells, detect and eliminate circulating tumor cells (CTCs)14. The various effector mechanisms involved in the antitumor activity of NK cells include perforin/granzyme-, death receptor-, and interferon (IFN)-γ-mediated pathways15. In the death receptor pathway, NK cells express members of the tumor necrosis factor (TNF) superfamily, including Fas ligand and TNF-related apoptosis-inducing ligand (TRAIL), and can induce cytotoxicity16–18. Liver NK cells comprise two distinct NK cell lineages: conventional NK (cNK) cells and tissue-resident NK cells. Regarding the tissue-resident population, the terminology varies among researchers, with the terms “liver-resident NK”(lrNK) cells and “type 1 innate lymphoid cells”(ILC1s) being used. As these cell populations share the same surface markers and exhibit similar characteristics, they are often treated as synonyms in the field19–21. Both lrNK cells and ILC1s express high levels ofTRAIL, which preferentially induces apoptotic cell death in various tumor cells17,22,23, and they show strong cytotoxicity against hepatoma cells with TRAIL death receptors12, 13.  \nWe previously demonstrated reduced TRAIL expression on liver NK cells following liver resection or transplantation, which contributed to diminished antitumor immunity13,24–27. We reported that th","cbCaisFqvaacWWfi","https://ap.wps.com/l/cbCaisFqvaacWWfi","pdf",5570461,"English","# Metformin and TRAIL on liver NK cells\n## Antitumor activity and prior evidence\n## Hypothesis and study aims\n## Experimental findings and mechanistic interpretation","[{\"question\":\"How does metformin influence liver natural killer (NK) cell antitumor activity?\",\"answer\":\"Metformin increases the proportion of TRAIL+ liver NK cells, enhances NK-cell cytotoxicity against TRAIL-sensitive tumor targets, and suppresses tumor growth in vivo.\"},{\"question\":\"What mechanistic pathway may mediate metformin’s effects on TRAIL+ liver NK cells?\",\"answer\":\"The AMPK signaling axis is implicated in promoting the increase of TRAIL+ liver NK-cell subsets.\"},{\"question\":\"What cell subsets are reported to expand after metformin treatment?\",\"answer\":\"Metformin increases a liver-resident NK-like (type 1 innate lymphoid cell, ILC1) Eomeslow, TRAILhigh subset.\"}]","Metformin enhances TRAIL-mediated antitumor activity of liver natural killer cells in mice | PDF",1790110025]