CD8⁺ Tissue-Resident Memory T Cells in Health and Disease

CD8⁺ tissue-resident memory T (T_RM) cells play a pivotal role in local immune regulation. These noncirculating T cells are uniquely positioned to orchestrate rapid site-specific immune responses, making them central to understanding tissue-specific immunity. Prior work has demonstrated that CD8⁺ T_RM cells possess dual functions: they are essential for immune defense against pathogens and malignancies, yet also drive pathological inflammation in autoimmune disorders. Furthermore, emerging evidence has begun to elucidate the intrinsic molecular mechanisms controlling this functional duality and to develop intervention strategies for its precise modulation. Here, we review current knowledge of the origin, transcriptional regulation, phenotypic characteristics, and functions of CD8⁺ T_RM cells. We discuss how T_RM cells correlate with clinical outcomes in diverse cancer types. Furthermore, we explore immune checkpoint inhibitors and other immunotherapies that target T_RM cells and their therapeutic implications from preclinical and translational human research. This review provides a comprehensive understanding of the molecular and cellular mechanisms governing T_RM cell activity and details their roles in health and disease. Ultimately, the framework of tissue immune networks reveals that leveraging T_RM cell development, tissue residency, and metabolism processes enables the design of innovative treatments for these diseases.