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We knocked down MEF2D in HCC cell lines and analyzed HCC tissues and cell lines by RNA sequencing, Western blot, and immunohistochemistry. Chromatin immunoprecipitation was used to analyze the regulation of CD70 transcription by MEF2D. HCC cells with or without MEF2D knockout were injected into the livers of syngeneic BALB\/c mice. Flow cytometry was used to analyze the function of T cells in tumors, spleens, and lymph nodes. We found that in contrast to wild-type tumors in immunocompetent mice, HCC with MEF2D knockdown had smaller tumors, increased T-cell activation, and impaired T regulatory (Treg) cell suppressive function. Mechanistically, MEF2D bound to the promoter region of CD70 gene and activated its transcription and this process was further enhanced by p300-induced MEF2D acetylation. CD70 blocking antibody inhibited activation of the CD70-CD27 signaling axis in murine HCC tumors, leading to impaired immunosuppressive function of Tregs and enhanced antitumor immunity. MEF2D blocks T-cell\u2013mediated antitumor immunity by regulating the expression of CD70 and activating the CD70-CD27 signaling axis. Strategies to manipulate this pathway may improve the efficacy of liver cancer immunotherapy.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf228","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T15:58:28Z","timestamp":1759161508000},"page":"3162-3178","source":"Crossref","is-referenced-by-count":1,"title":["MEF2D regulates T-cell function via CD70-CD27 signaling and promotes immune evasion in hepatocellular carcinoma"],"prefix":"10.1093","volume":"214","author":[{"given":"Fanhua","family":"Kong","sequence":"first","affiliation":[{"name":"Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials , Wuhan, Hubei,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Philadelphia , Philadelphia, PA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongshan","family":"Lu","sequence":"additional","affiliation":[{"name":"Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials , Wuhan, Hubei,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiakang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials , Wuhan, Hubei,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qifa","family":"Ye","sequence":"additional","affiliation":[{"name":"Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials , Wuhan, Hubei,","place":["China"]},{"name":"The Third Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology , Changsha, Hunan,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne W","family":"Hancock","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials , Wuhan, Hubei,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"2025112603025712900_vkaf228-B1","doi-asserted-by":"crossref","first-page":"5464","DOI":"10.7150\/thno.54822","article-title":"Current status of sorafenib nanoparticle delivery systems in the treatment of hepatocellular carcinoma","volume":"11","author":"Kong","year":"2021","journal-title":"Theranostics"},{"key":"2025112603025712900_vkaf228-B2","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1186\/s12906-023-04244-w","article-title":"Mechanism underlying the effect of Pulsatilla decoction in hepatocellular carcinoma treatment: a network pharmacology and in vitro analysis","volume":"23","author":"Liu","year":"2023","journal-title":"BMC 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