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This study uses in vitro G6PD knockdown in malignant melanoma, GEO pathway analysis, in vivo experiments combining G6PD inhibition with immune checkpoint inhibitors in a mouse melanoma model, and prognostic analyses in 42 melanoma and 30 lung cancer patients treated with ICIs. G6PD inhibition reduces NADPH production and oxidative stress tolerance, promoting cell death marked by HMGB1 release and calreticulin translocation, with improved responses and patient survival outcomes.",{"@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/blockade-of-glucose-6-phosphate-dehydrogenase-induces-immunogenic-cell-death-and-accelerates-immunotherapy/331069/",{"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/blockade-of-glucose-6-phosphate-dehydrogenase-induces-immunogenic-cell-death-and-accelerates-immunotherapy/331069.png","ImageObject",300,407,{"name":92,"@type":93},"Oliver","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},"What is the main biological pathway involving G6PD discussed in the study?","Question",{"text":112,"@type":113},"G6PD is described as a rate-limiting enzyme in the pentose phosphate pathway that maintains NADPH levels and protects cells from oxidative damage.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does G6PD inhibition trigger immunogenic cell death?",{"text":117,"@type":113},"Inhibition of G6PD decreases NADPH production and reduces oxidative stress tolerance, leading to cell death accompanied by HMGB1 release and calreticulin translocation to the plasma membrane.",{"name":119,"@type":110,"acceptedAnswer":120},"What evidence supports the clinical relevance of low G6PD expression?",{"text":121,"@type":113},"In patients treated with immune checkpoint inhibitors, low G6PD expression is associated with a better prognosis in 42 melanoma patients and 30 lung cancer patients, with reported p-values.","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},331069,1790177045,{"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":41,"preview_page_count":4},8796095461610,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Open access Original research  \nTo cite: Nakamura M, Magara T, Yoshimitsu M, et al. Blockade of glucose-6-phosphate dehydrogenase induces immunogenic cell death and accelerates  \nimmunotherapy. Journal for ImmunoTherapy of Cancer 2024;12:e008441 . doi:10 . 1136/ jitc-2023-008441  \nAccepted 07 July 2024  \n© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.  \n1Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan 2Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan  \nCorrespondence to  \nDr Motoki Nakamura;  \n[motoki1@med.nagoya-cu.ac.jp](motoki1@med.nagoya-cu.ac.jp)  \nBlockade of glucose-6-phosphate dehydrogenase induces immunogenic cell death and accelerates immunotherapy  \nMotoki Nakamura  ,1 Tetsuya Magara,1 Maki Yoshimitsu,1 Shinji Kano,1 Hiroshi Kato,1 Keisuke Yokota,2 Katsuhiro Okuda,2 Akimichi Morita1  \nABSTRACT  \nBackground Enhanced glucose metabolism has  \nbeen reported in many cancers. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme involved in the pentose phosphate pathway, which maintains NADPH levels and protects cells from oxidative damage. We recently found that low G6PD expression correlates with active tumor immunity. However, the mechanism involving G6PD and tumor immunity remained unclear. Methods We conducted in vitro studies using G6PDknocked down malignant melanoma cells, pathway analysis using the GEO dataset, in vivo studies in combination with immune checkpoint inhibitors (ICIs) using a mouse melanoma model, and prognostic analysis in 42 melanoma patients and 30 lung cancer patients who were treated with ICIs.  \nResults Inhibition of G6PD, both chemically and genetically, has been shown to decrease the production of NADPH and reduce their oxidative stress tolerance.  \nThis leads to cell death, which is accompanied by the release of high mobility group box 1 and the translocation of calreticulin to the plasma membrane. These findings suggested that inhibiting G6PD can induce immunogenic cell death. In experiments with C57BL/6 mice transplanted with G6PD-knockdown B16 melanoma cells and treated with anti-PD-L1 antibody, a significant reduction in tumor size was observed. Interestingly, inhibiting G6PD in only apart of the lesions increased the sensitivity of other lesions to ICI. Additionally, out of 42 melanoma patients and 30 lung cancer patients treated with ICIs, those with low G6PD expression had a better prognosis than those with high G6PD expression (p=0 .0473; melanoma, p=0 .0287; lung cancer) .  \nConclusion G6PD inhibition is a potent therapeutic strategy that triggers immunogenic cell death in tumors, significantly augmenting the efficacy of immunotherapies.  \nINTRODUCTION  \nOur recent studies in Merkel cell carcinoma revealed that the intensity of glucose- 6-phosphate dehydrogenase (G6PD) expression is an indicator of tumor typing based on immune activity and inversely correlates with programmed death ligand-1 (PD-L1) expression in tumor cells and  \nWHAT IS ALREADY KNOWN ON THIS TOPIC  \n\n| ⇒ Enhanced glucose metabolism including pentose phosphate pathway in tumors is known and inhibition of glucose-6-phosphate dehydrogenase (G6PD) as a strategy in cancer therapy is tried. In our previous reports, low G6PD expression correlates with activated tumor immunity. However, the mechanism involving G6PD and tumor immunity remained unclear.\u003Cbr>WHAT THIS STUDY ADDS |\n| --- |\n| ⇒ This study reveals a mechanism linking G6PD and tumor immunity: G6PD protects cancer cells from immunogenic cell death (ICD), and induction of ICD by G6PD inhibition is a novel therapeutic strategy.\u003Cbr>HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY |\n\n⇒ Although G6PD inhibition alone has so far failed to lead to practical application, this study shows th","cbCaihbA11bFs40T","https://ap.wps.com/l/cbCaihbA11bFs40T","pdf",8345400,12,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusion\n# What is already known on this topic\n# What this study adds\n# How this study might affect research, practice or policy","[{\"question\":\"What is the main biological pathway involving G6PD discussed in the study?\",\"answer\":\"G6PD is described as a rate-limiting enzyme in the pentose phosphate pathway that maintains NADPH levels and protects cells from oxidative damage.\"},{\"question\":\"How does G6PD inhibition trigger immunogenic cell death?\",\"answer\":\"Inhibition of G6PD decreases NADPH production and reduces oxidative stress tolerance, leading to cell death accompanied by HMGB1 release and calreticulin translocation to the plasma membrane.\"},{\"question\":\"What evidence supports the clinical relevance of low G6PD expression?\",\"answer\":\"In patients treated with immune checkpoint inhibitors, low G6PD expression is associated with a better prognosis in 42 melanoma patients and 30 lung cancer patients, with reported p-values.\"}]","Blockade of glucose-6-phosphate dehydrogenase induces immunogenic cell death and accelerates immunotherapy | PDF",1789991548]