{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T07:49:22Z","timestamp":1791791362313,"version":"4.3.4"},"reference-count":35,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100017950","name":"Shanghai Municipal Health Commission","doi-asserted-by":"publisher","award":["202240272"],"award-info":[{"award-number":["202240272"]}],"id":[{"id":"10.13039\/100017950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Asia-Pac J Clncl Oncology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Targeting CD147 on hepatocellular carcinoma (HCC) cells has demonstrated therapeutic efficacy. Cancer\u2010associated fibroblasts (CAFs) have been identified as critical components of the tumor microenvironment. The role of CD147 in CAFs is still unclear, and this study aims to explore its function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed single\u2010cell RNA\u2010seq data to identify CD147 expression in CAFs. Flow cytometry and multiplex immunohistochemistry (mIHC) were used to validate protein levels. CD147 function was assessed via shRNA\/overexpression. Protein interactions were examined by molecular docking and co\u2010immunoprecipitation (Co\u2010IP). Organoid co\u2010culture system was established to study tumor\u2010immune interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Single\u2010cell sequencing and mIHC analyses have confirmed the presence of CD147+CAFs within tumor and adjacent tissues, with tumor\u2010derived CAFs exhibiting elevated CD147 transcript levels. The proportion of CD147+ CAFs varied among patients and demonstrated no significant correlation with CD147 expression in HCC cells. Functionally, CD147+ CAFs secreted higher levels of IL\u20106 compared to CD147\u2010 counterparts. We elucidated a mechanism wherein CD147 on CAFs competitively binds to the tissue inhibitor of metalloproteinase 2 (TIMP2), thereby diminishing TIMP2\u2010mediated inhibition of matrix metalloproteinase 2 (MMP2). Free MMP2 enhances IL\u20106 secretion via the integrin \u03b15\u03b21 signaling pathway. IL\u20106 subsequently upregulates PD\u2010L1 expression on HCC cells. This phenomenon was validated both in vitro and organoid co\u2010culture model, where a higher burden of CD147+ CAFs correlated with increased levels of IL\u20106 and PD\u2010L1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study delineates a novel CAF\u2010driven immunosuppressive pathway in HCC, where CD147+ CAFs enhance tumor cell PD\u2010L1 expression and susceptibility to immune checkpoint blockade via a TIMP2\/MMP2\/IL\u20106 axis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Significance<\/jats:title>\n                    <jats:p>CD147 has been primarily viewed as a therapeutic marker on HCC cells and has supported the development of CD147\u2010targeted treatment strategies. This study shows that CD147 is also expressed in CAFs and functions as an independent regulator of the immune microenvironment by promoting IL 6 secretion and tumor PD\u2010L1 upregulation. Importantly, CD147 expression in CAFs is not correlated with its expression in tumor cells. These findings suggest that evaluation of CD147 in both tumor and stromal compartments may improve patient stratification and may identify additional patients who could potentially benefit from CD147\u2010targeted or combination immunotherapy approaches.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ajco.70177","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T07:35:04Z","timestamp":1791790504000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD147+ Cancer\u2010Associated Fibroblasts Promote PD\u2010L1 Expression in Hepatocellular Carcinoma via TIMP2\/MMP2\/IL\u20106 Signaling"],"prefix":"10.1111","author":[{"given":"Yifei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Hepatic Surgery Eastern Hepatobiliary Surgery Hospital Naval Medical University  Shanghai 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