Tissue-resident memory CD8⁺ T cells: master deciphers of the hepatic environment

Tissue-resident memory CD8⁺ T (CD8⁺ T_RM) 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⁺ T_RM 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⁺ T_RM 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⁺ T_RM 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⁺ T_RM cells and how the enhanced functionality of CD8⁺ T_RM cells can be harnessed therapeutically in the context of hepatocellular carcinoma.