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This research identifies CXCL2 downregulation in HCC as driven by gene copy number loss, linking reduced CXCL2 to poor prognosis and diminished immunotherapy responsiveness. CXCL2 recruits neutrophils and polarizes them toward an antitumor phenotype. Mechanistically, intracellular CXCL2 binds YBX1, blocks its nuclear translocation, lowers SREBF2 transcription, suppresses cholesterol biosynthesis, and reshapes the HCC microenvironment to hinder tumor progression.",{"@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/tumor-cell-derived-cxcl2-potentiates-neutrophil-mediated-antitumor-immunity-by-inhibiting-cholesterol-biosynthesis-in-hepatocellular-carcinoma/469572/",{"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/tumor-cell-derived-cxcl2-potentiates-neutrophil-mediated-antitumor-immunity-by-inhibiting-cholesterol-biosynthesis-in-hepatocellular-carcinoma/469572.png","ImageObject",300,407,{"name":92,"@type":93},"Alexandar","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-30",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},"What role does CXCL2 play in hepatocellular carcinoma according to the study?","Question",{"text":112,"@type":113},"CXCL2 is downregulated in HCC due to gene copy number loss, and lower levels correlate with poor prognosis and weak immunotherapy responsiveness. The study also shows CXCL2 can recruit neutrophils and shift them toward an antitumor polarization state.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does CXCL2 influence neutrophils to inhibit tumor progression?",{"text":117,"@type":113},"The study finds CXCL2 not only recruits neutrophils but induces their polarization toward an antitumor type, which helps curb HCC progression.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism connects CXCL2 to cholesterol biosynthesis and immune remodeling?",{"text":121,"@type":113},"Intracellular CXCL2 binds YBX1 and prevents its nuclear translocation, reducing SREBF2 transcription. This suppresses cholesterol biosynthesis, thereby remodeling the HCC microenvironment and impeding development.","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},469572,1791496789,{"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":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,"preview_page_count":4},962090768658,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","RESEARCH ARTICLE  \n[www.advancedscience.com](www.advancedscience.com)  \nTumor Cell-Derived CXCL2 Potentiates Neutrophil-Mediated Antitumor Immunity by Inhibiting Cholesterol Biosynthesis in Hepatocellular Carcinoma  \nXin Liu, Danli Yang, Qianqian Jiang, Meng Han, Zhao Zhou, Yukun Li, Yu Wu, Jingzhou Wang, Ting Zhang, Guohua Lou, Guochao Wei, Lin Wang,* Fengmin Lu,* and Xiangmei Chen*  \nHepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Despite the proven efficacy of immunotherapy against malignancies, a large proportion of patients with HCC fail to benefit from these efficacious agents because of their overwhelmingly immunosuppressive microenvironment. Therefore, there is an urgent need to identify key genes and develop effective strategies for reshaping the HCC microenvironment. Here, a significant downregulation ofC-X-C motif chemokine ligand 2 (CXCL2) in HCC is identified due to gene copy number loss, which correlates with poor prognosis and suboptimal responsiveness to immunotherapy. Subsequently, it is found that CXCL2 can not only recruit neutrophils as expected, but also induce their polarization toward the antitumor type to curb HCC progression. Mechanistically, differing from the prevailing notion that CXCL2 primarily functions extracellularly as a chemokine, it is demonstrated that intracellular CXCL2 can bind to Y-Box Binding Protein 1 (YBX1) and prevent its nuclear translocation. Consequently, this reduces the transcription of sterol regulatory element binding transcription factor 2 (SREBF2) and suppresses cholesterol biosynthesis, thereby remodeling HCC microenvironment and impeding HCC development. In summary, this study highlights the unconventional role of CXCL2 in regulating neutrophil polarization and immune responses in HCC, positioning it as a potential therapeutic target for HCC.  \n1. Introduction  \nHepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide and is characterized by a complex interplay between genetic mutations, environmental factors, and immune system interactions. [1] Despite advances in HCC therapeutics, the prognosis of HCC remains challenging due to its late-stage diagnosis and early metastasis or recurrence. In recent years, many studies have illuminated the crucial role of immunotherapy in treating malignancies. [2,3] However, a majority of patients with HCC cannot benefit from such effective agents due to their overwhelmingly immunosuppressive microenvironment. [4] Therefore, it is an urgent need to find effective ways to reshape the microenvironment.  \nCopy number variations (CNV), defined as an amplification or decrease in the number of DNA segments that are 1 kb or larger in the human genome, are frequent events in tumors. [5,6] Previous studies have  \nX. Liu, D. Yang, Z. Zhou, Y. Li, Y. Wu, J. Wang, T. Zhang, G. Wei, L. Wang, F. Lu, X. Chen  \nDepartment of Microbiology and Infectious Disease Research Center School of Basic Medical Sciences  \nPeking University Health Science Center  \nBeijing 100191, China  \nE-mail: [lin_wang@pku.edu.cn](lin_wang@pku.edu.cn); [lu.fengmin@hsc.pku.edu.cn](lu.fengmin@hsc.pku.edu.cn);  \n[xm_chen6176@bjmu.edu.cn](xm_chen6176@bjmu.edu.cn)  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202511436](https://doi.org/10.1002/advs.202511436)[ ](https://doi.org/10.1002/advs.202511436)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nDOI: 10.1002/advs.202511436  \nQ. Jiang  \nPeking University Hepatology Institute Peking University People’s Hospital Beijing 100044, China  \nM. Han  \nDepartment of Laboratory Medicine  \nThe First Affiliated Hospital of Zhengzhou University Zhengzhou 450052, China  \nG. Lou  \nState Key Laborat","cbCaicBfAPBEN9LU","https://ap.wps.com/l/cbCaicBfAPBEN9LU","pdf",11118504,14,"English","# Introduction\n## Immunosuppressive microenvironment in HCC\n## CNVs and gene dysregulation in tumors\n# Results Overview\n## CXCL2 downregulation and prognostic value\n## CXCL2 effects on neutrophil recruitment and polarization\n## Intracellular CXCL2-YBX1-SREBF2 axis and cholesterol biosynthesis\n# Conclusion and Therapeutic Implications","[{\"question\":\"What role does CXCL2 play in hepatocellular carcinoma according to the study?\",\"answer\":\"CXCL2 is downregulated in HCC due to gene copy number loss, and lower levels correlate with poor prognosis and weak immunotherapy responsiveness. The study also shows CXCL2 can recruit neutrophils and shift them toward an antitumor polarization state.\"},{\"question\":\"How does CXCL2 influence neutrophils to inhibit tumor progression?\",\"answer\":\"The study finds CXCL2 not only recruits neutrophils but induces their polarization toward an antitumor type, which helps curb HCC progression.\"},{\"question\":\"What mechanism connects CXCL2 to cholesterol biosynthesis and immune remodeling?\",\"answer\":\"Intracellular CXCL2 binds YBX1 and prevents its nuclear translocation, reducing SREBF2 transcription. This suppresses cholesterol biosynthesis, thereby remodeling the HCC microenvironment and impeding development.\"}]","Tumor Cell-Derived CXCL2 Potentiates Neutrophil-Mediated Antitumor Immunity by Inhibiting Cholesterol Biosynthesis in Hepatocellular Carcinoma | PDF",1790775861,35]