The Janus face of tissue-resident memory T cells: dual programming in tumor immune surveillance and autoimmune pathology

Tissue-resident memory T cells (Trm) are a subset of memory T cells that establish residency in peripheral tissues and do not re-enter circulation under homeostasis, playing a central role in local immune responses. Recent studies have revealed that Trm cells play a dual role in immune protection and immunopathology: in the tumor microenvironment they can directly kill tumor cells and enhance the efficacy of immunotherapies, serving as key mediators of antitumor immunity; conversely, in autoimmune diseases they may persist long-term and drive chronic inflammation and tissue damage. This functional duality is closely linked to the microenvironmental signals, transcriptional programs, and metabolic states that shape Trm cells. This review systematically examines the developmental differentiation and molecular features of Trm cells, their bidirectional regulatory mechanisms in cancer and autoimmunity, and outlines the therapeutic potential and challenges of precision disease interventions targeting Trm cells.