Abstract
Tissue-resident memory CD8+ T (CD8+ TRM) cells are localized within peripheral tissues, such as the liver, poised to provide effective immunosurveillance, as well as rapid and enhanced effector functions upon stimulation. Here we review how hepatic CD8+ TRM cells decipher a myriad of environmental signals, ranging from cellular and soluble factors to direct interactions with the underlying stroma and structural tissue niche, which dictate their derivation, retention and function. We discuss insights from both mouse and human studies that have contributed to our understanding of how CD8+ TRM cells can, depending on the context, provide targeted antigen-specific antiviral and antitumour immune responses and elicit antigen-independent tissue-damaging responses that contribute to liver pathology. Specifically, we discuss how the CD8+ TRM cell functional response is shaped by multiple factors and how such environmental cues tip the balance between these dual ‘Jekyll and Hyde’ response modes. Finally, we examine strategies to better identify and characterize hepatic CD8⁺ TRM cells and how the enhanced functionality of CD8+ TRM cells can be harnessed therapeutically in the context of hepatocellular carcinoma.
Key points
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A population of long-lived hepatic CD8+ T cells interpret, integrates and responds to various environmental signals, ranging from metabolic and soluble mediators to direct cell–cell or cell–extracellular matrix interactions.
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Localized tissue-resident memory CD8+ T (CD8+ TRM) cells can elicit both immunoprotective and immunopathogenic effector functions within the liver.
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The functional response mode of hepatic CD8+ TRM cells is shaped and/or regulated by context-specific cues.
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The enhanced retention within tumours and rapid effector function of CD8+ TRM cells could be harnessed for therapeutic intervention, such as chimeric antigen receptor T cell therapy for hepatocellular carcinoma.
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The authors thank M. Maini, P. Knolle, A. Zhuang, A. Das, D. Wohlleber and B. Höchst for their critical review and discussion of the manuscript before submission.
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All authors researched data for the article. L.J.P. and M.D. contributed substantially to discussion of the content. All authors wrote the article. L.J.P. and M.D. reviewed and/or edited the manuscript before submission.
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Brown Romero, D., Finney, G.E., Dudek, M. et al. Tissue-resident memory CD8+ T cells: master deciphers of the hepatic environment. Nat Rev Gastroenterol Hepatol (2025). https://doi.org/10.1038/s41575-025-01118-z
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DOI: https://doi.org/10.1038/s41575-025-01118-z
