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This review synthesizes current knowledge of STAT3 signaling, covering positive and negative modulators, cancer hallmarks shaped by STAT3, and its highly sophisticated regulation of tumor microenvironment immunosuppression and metabolic reprogramming. Direct and indirect STAT3 inhibitors in preclinical and clinical studies are summarized, alongside proposed strategies and combinations with established therapies.",{"@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/unraveling-the-complexity-of-stat3-in-cancer-molecular-understanding-discovery-review/330000/",{"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/unraveling-the-complexity-of-stat3-in-cancer-molecular-understanding-discovery-review/330000.png","ImageObject",300,407,{"name":92,"@type":93},"Logic","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-24","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is STAT3 considered a promising therapeutic target in cancer?","Question",{"text":112,"@type":113},"STAT3 participates in major cancer hallmark features such as proliferation, metastasis, angiogenesis, immunosuppression, inflammation, metabolic reprogramming, drug resistance, and cancer stemness, which makes it a strong target for therapy.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What does the review cover regarding STAT3 signaling?",{"text":117,"@type":113},"It summarizes up-to-date STAT3 signaling knowledge, including both positive and negative modulators, the cancer hallmarks regulated by STAT3, and how STAT3 regulates immunosuppression in the tumor microenvironment and metabolic reprogramming.",{"name":119,"@type":110,"acceptedAnswer":120},"Does the review discuss STAT3 inhibitors and combination strategies?",{"text":121,"@type":113},"Yes. 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J Exp Clin Cancer Res (2024) 43:23 [https://doi.org/10.1186/s13046-024-02949-5](https://doi.org/10.1186/s13046-024-02949-5)  \nJournal of Experimental & Clinical Cancer Research  \n REVIEW Open Access  \nUnraveling the complexity of STAT3 in cancer: molecular understanding discovery  \nYamei Hu1,2, Zigang Dong1,3,6* and Kangdong Liu 1,3,4,5,6*  \nand drug  \nAbstract  \nSignal transducer and activator of transcription 3 (STAT3) is a transcriptional factor involved in almost all cancer hallmark features including tumor proliferation, metastasis, angiogenesis, immunosuppression, tumor inflammation, metabolism reprogramming, drug resistance, cancer stemness. Therefore, STAT3 has become a promising therapeutic target in a wide range of cancers. This review focuses on the up-to-date knowledge of STAT3 signaling in cancer. We summarize both the positive and negative modulators of STAT3 together with the cancer hallmarks involving activities regulated by STAT3 and highlight its extremely sophisticated regulation on immunosuppression in tumor microenvironment and metabolic reprogramming. Direct and indirect inhibitors of STAT3 in preclinical and clinical studies also have been summarized and discussed. Additionally, we highlight and propose new strategies of targeting STAT3 and STAT3-based combinations with established chemotherapy, targeted therapy, immunotherapy and combination therapy. These efforts may provide new perspectives for STAT3-based target therapy in cancer.  \nKeywords STAT3, Cancer, Modulators, Metabolic reprogramming, Immunosuppression, Inhibitors  \n*Correspondence: Zigang Dong [zgdong@hci-cn.org](zgdong@hci-cn.org)[ ](zgdong@hci-cn.org)Kangdong Liu[kdliu@zzu.edu.cn](kdliu@zzu.edu.cn)  \n1 Tianjian Laboratory for Advanced Biomedical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China  \n2 Medical Research Center, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, Henan, China  \n3 China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, Henan, China  \n4 State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China  \n5 Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou, Henan, China  \n6 Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China  \nIntroduction  \nSTAT3 belongs to the STATs family and comprises STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6 that share similar structures and functional domains [1]. STAT3 is one of the most well-described STATs members and which mainly acts as tumor promoting roles in tumor development and progression. Apart from the canonical functions such as proliferation, apoptosis, metastasis, angiogenesis, drug resistance, selfrenewal of cancer stemness, the newly identified functions such as epigenetic regulation, immune surveillance, tumor inflammation, metabolic reprogramming and exosome-related biological activities also contribute to the oncogenic roles in cancer.  \nSTAT3 historically has been considered “undruggable”. However, the current development of advanced technologies and novel therapeutic strategies in STAT3 inhibitors has moved toward “druggable”. A series of selective inhibitors that directly or indirectly  \n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exc","cbCaik0O9MnclRnl","https://ap.wps.com/l/cbCaik0O9MnclRnl","pdf",2190669,29,"English","# Introduction\n## Overall reviews of STAT3\n## Isoforms of STAT3","[{\"question\":\"Why is STAT3 considered a promising therapeutic target in cancer?\",\"answer\":\"STAT3 participates in major cancer hallmark features such as proliferation, metastasis, angiogenesis, immunosuppression, inflammation, metabolic reprogramming, drug resistance, and cancer stemness, which makes it a strong target for therapy.\"},{\"question\":\"What does the review cover regarding STAT3 signaling?\",\"answer\":\"It summarizes up-to-date STAT3 signaling knowledge, including both positive and negative modulators, the cancer hallmarks regulated by STAT3, and how STAT3 regulates immunosuppression in the tumor microenvironment and metabolic reprogramming.\"},{\"question\":\"Does the review discuss STAT3 inhibitors and combination strategies?\",\"answer\":\"Yes. It summarizes direct and indirect STAT3 inhibitors from preclinical and clinical studies and highlights proposed strategies, including STAT3-based combinations with chemotherapy, targeted therapy, immunotherapy, and combination therapy.\"}]","Unraveling the complexity of STAT3 in cancer - molecular understanding discovery - review | PDF",1789986494,73]