Tissue-resident memory T cells: resilient sentinels in cancer immunosurveillance and immunotherapy

Tissue-resident memory T (T RM ) cells represent a specialized subset of memory T cells defined by their long-term residency in peripheral non-lymphoid tissues, where they provide frontline immune surveillance at barrier sites such as the skin, intestines, lungs, and liver. Accumulating evidence has identified CD69 + CD103 + tumor-infiltrating lymphocytes exhibiting canonical T RM phenotypes across diverse cancers, where their abundance and functional states have been linked to anti-tumor immunity and predictors of favorable clinical outcomes. In this review, we synthesize current knowledge on T RM biology with a focus on their roles in cancer immunology. We first delineate core phenotypic markers and trace the differentiation trajectory of naïve T cells into T RM cells, highlighting tissue-specific developmental pathways. We then integrate molecular mechanisms, including transcription factor and epigenetic networks, cytokine cues, metabolic reprogramming toward lipid oxidation, and multicellular crosstalk, that collectively enforce T RM residency and function within the tumor microenvironment. Recognizing the heterogeneity of tumor-associated T RM -like TILs, we discuss their abundance, phenotypic features, and functional states, while examining their relationships with bystander and exhausted T cell populations across cancers. Finally, we evaluate the translational potential of T RM cells as predictive biomarkers for immune checkpoint blockade and as engineering targets for next-generation adoptive cell therapies and cancer vaccines. Collectively, this review offers a timely, mechanism-to-bedside framework for understanding how T RM cells bridge tissue immunity and cancer immunotherapy.