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Cancer stem cells (CSCs) drive tumor growth and contribute to therapeutic resistance by secreting soluble paracrine factors. This review updates how CSC-derived secretory factors, including growth factors, cytokines, chemokines, and exosomes, shape an immunosuppressive TME that promotes immune resistance. It also summarizes current strategies targeting these factors and outlines future directions, supporting rational combination approaches with ICIs for more effective HCC treatment.",{"@graph":69,"@context":123},[70,84,106],{"@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/the-roles-of-cancer-stem-cell-derived-secretory-factors-in-shaping-the-immunosuppressive-tumor-microenvironment-in-hepatocellular-carcinoma/333439/",{"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/the-roles-of-cancer-stem-cell-derived-secretory-factors-in-shaping-the-immunosuppressive-tumor-microenvironment-in-hepatocellular-carcinoma/333439.png","ImageObject",300,407,{"name":92,"@type":93},"Ivy","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why are immune checkpoint inhibitors less effective in hepatocellular carcinoma?","Question",{"text":113,"@type":114},"Their response rates are modest because the HCC tumor microenvironment is immunosuppressive, limiting anti-tumor immune activity.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How do cancer stem cells contribute to the immunosuppressive tumor microenvironment?",{"text":118,"@type":114},"Cancer stem cells support tumor growth and therapeutic resistance by secreting multiple soluble paracrine factors that modulate cellular and physical conditions within the tumor niche.",{"name":120,"@type":111,"acceptedAnswer":121},"Which types of CSC-derived secretory factors are discussed in the review?",{"text":122,"@type":114},"The review highlights growth factors, cytokines, chemokines, and exosomes as key contributors to the immunosuppressive TME and immune resistance.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},333439,1790488037,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},549758252649,"https://ap-avatar.wpscdn.com/avatar/8000253669c5317157?_k=1778319167496531819","TYPE Review  \nPUBLISHED 29 May 2024  \nDOI 10.3389/fimmu.2024.1400112  \nOPEN ACCESS  \nEDITED BY  \nRosanna Paciucci,  \nVall d’ Hebron University Hospital, Spain  \nREVIEWED BY Zhenbo Tu,  \nBeth Israel Deaconess Medical Center, United States  \nSaptak Banerjee,  \nChittaranjan National Cancer Institute (CNCI), India  \n*CORRESPONDENCE Terence Kin-Wah Lee  \n [terence.kw.lee@polyu.edu.hk](terence.kw.lee@polyu.edu.hk)  \nRECEIVED 13 March 2024  \nACCEPTED 15 May 2024  \nPUBLISHED 29 May 2024  \nCITATION  \nMuliawan GK and Lee TK-W (2024) The roles of cancer stem cell-derived  \nsecretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma.  \nFront. Immunol. 15:1400112 .  \ndoi: 10.3389/fimmu.2024.1400112  \nCOPYRIGHT  \n© 2024 Muliawan and Lee. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nThe roles of cancer stem cellderived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma  \nGregory Kenneth Muliawan 1 and Terence Kin-Wah Lee 1,2*  \n1 Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China, 2State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China  \nHepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and has a poor prognosis. Although immune checkpoint inhibitors have entered a new era of HCC treatment, their response rates are modest, which can be attributed to the immunosuppressive tumor microenvironment within HCC tumors. Accumulating evidence has shown that tumor growth is fueled by cancer stem cells (CSCs), which contribute to therapeutic resistance to the above treatments. Given that CSCs can regulate cellular and physical factors within the tumor niche by secreting various soluble factors in a paracrine manner, there have been increasing efforts toward understanding the roles of CSCderived secretory factors in creating an immunosuppress ive tumor microenvironment. In this review, we provide an update on how these secretory factors, including growth factors, cytokines, chemokines, and exosomes, contribute to the immunosuppressive TME, which leads to immune resistance. In addition, we present current therapeutic strategies targeting CSCderived secretory factors and describe future perspectives. In summary, a better understanding of CSC biology in the TME provides a rational therapeutic basis for combination therapy with ICIs for effective HCC treatment.  \nKEYWORDS  \ncancer stem cell (CSC), hepatocellular carcinoma, immunosuppression, secretory factors, tumor microenvironment  \n1 Introduction to hepatocellular carcinoma  \nCancer has long been a major public health concern, with consistently increasing incidence and mortality rates worldwide. According to GLOBOCAN estimation data for 2020, a total of 19 million new cancer cases and 10 million cancer-related deaths are predicted to occur globally (1) . Primary liver cancer is the sixth most diagnosed cancer and  \nFrontiers in Immunology 01 [frontiersin.org](frontiersin.org)  \nthe third leading cause of cancer-related deaths worldwide according to GLOBOCAN 2020 evaluations (1) . Liver cancer has been established as one of the key contributors to the global cancer burden, and hepatocellular carcinoma (HCC) is one of the most commonly diagnosed histological subtypes of liver malignancy, accounting for approximately 80% of all liver cancer cases worldwide (2) . Despite the significance of HCC cases in transitioning countries with low and m","cbCaimPNvui7Fn8C","https://ap.wps.com/l/cbCaimPNvui7Fn8C","pdf",2229899,17,"English","# Introduction to hepatocellular carcinoma\n## Epidemiology and risk factors\n# Therapeutic options for hepatocellular carcinoma patients","[{\"question\":\"Why are immune checkpoint inhibitors less effective in hepatocellular carcinoma?\",\"answer\":\"Their response rates are modest because the HCC tumor microenvironment is immunosuppressive, limiting anti-tumor immune activity.\"},{\"question\":\"How do cancer stem cells contribute to the immunosuppressive tumor microenvironment?\",\"answer\":\"Cancer stem cells support tumor growth and therapeutic resistance by secreting multiple soluble paracrine factors that modulate cellular and physical conditions within the tumor niche.\"},{\"question\":\"Which types of CSC-derived secretory factors are discussed in the review?\",\"answer\":\"The review highlights growth factors, cytokines, chemokines, and exosomes as key contributors to the immunosuppressive TME and immune resistance.\"}]","The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma | PDF",1790002458,43]