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While immunotherapy has transformed the landscape of cancer treatment, its success is often limited by immune resistance, particularly through T cell exhaustion which remains a major barrier to effective immune responses in solid tumours, including HCC. As tumours progress, T cells undergo a gradual loss of functionality due to continuous antigen exposure and fail to exert effective anti\u2010tumour responses. During this process, alterations in the epigenome, transcriptome, signalling pathways, and tumour metabolome, in addition to interactions with other cells in the tumour microenvironment, efficiently contribute to T cell exhaustion. Restoring T cell function brings hope for improving therapy outcomes and providing new treatment modalities for HCC patients. In this review, we explore the key cellular and molecular mechanisms driving T cell exhaustion, including the roles of immunosuppressive cells, metabolic stress, and epigenetic alterations focusing on HCC. We also discuss current and emerging strategies aimed at preventing or reversing T cell exhaustion, such as epigenetic modulation, immune checkpoint blockade, metabolic reprogramming, and combination therapies. Understanding these interconnected pathways is critical for designing more effective immunotherapy\u2010based approaches for liver cancer.<\/jats:p>","DOI":"10.1111\/jcmm.71044","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T08:13:12Z","timestamp":1770365592000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["T Cell Exhaustion in Hepatocellular Carcinoma: A Substantial Barrier in Immunotherapy"],"prefix":"10.1111","volume":"30","author":[{"given":"Kosar","family":"Nouri","sequence":"first","affiliation":[{"name":"Department of Regenerative Medicine, Cell Science Research Center Royan Institute for Stem Cell Biology and Technology, ACECR  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Negar","family":"Asadollahei","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Cell Science Research Center Royan Institute for Stem Cell Biology and Technology, ACECR  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasamin","family":"Haghir\u2010Sharif\u2010Zamini","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Cell Science Research Center Royan Institute for Stem Cell Biology and Technology, ACECR  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Homeyra","family":"Seydi","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Cell Science Research Center Royan Institute for Stem Cell Biology and Technology, ACECR  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahsa","family":"Salehi","sequence":"additional","affiliation":[{"name":"Biological Products and Blood Safety Research Center High Institute for Research and Education in Transfusion Medicine  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrnaz","family":"Mesdaghi","sequence":"additional","affiliation":[{"name":"Department of Allergy and Clinical Immunology Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences  Tehran Iran"},{"name":"Department of Immunology, School of Medicine Shahid Beheshti University of Medical Sciences  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7329-9635","authenticated-orcid":false,"given":"Mustapha","family":"Najimi","sequence":"additional","affiliation":[{"name":"Laboratory of Pediatric Hepatology and Cell Therapy Institute of Experimental and Clinical Research, UCLouvain  Brussels Belgium"},{"name":"Private University of Marrakesh  Marrakesh Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5924-4366","authenticated-orcid":false,"given":"Massoud","family":"Vosough","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Cell Science Research Center Royan Institute for Stem Cell Biology and Technology, ACECR  Tehran Iran"},{"name":"Experimental Cancer Medicine, Institution for Laboratory Medicine Karolinska Institute  Stockholm Sweden"},{"name":"Department of Medical Biotechnology, School of Advanced Technologies in Medicine Tehran University of Medical Sciences  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29913"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v29.i6.1054"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1905675116"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21155456"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-21-0515"},{"issue":"670","key":"e_1_2_15_8_1","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.abn7336","article-title":"BLIMP1 and NR4A3 Transcription Factors Reciprocally Regulate Antitumor CAR T Cell Stemness and Exhaustion","volume":"14","author":"Jung I. 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