Resident memory T cells in tumor-distant tissues fortify against metastasis formation

As a critical machinery for rapid pathogen removal, resident memory T cells (T_RMs) are locally generated after the initial encounter. However, their development accompanying tumorigenesis remains elusive. Using a murine breast cancer model, we show that T_RMs develop in the tumor, the contralateral mammary mucosa, and the pre-metastatic lung. Single-cell RNA sequencing of T_RMs reveals two phenotypically distinct populations representing their active versus quiescent phases. These T_RMs in different tissue compartments share the same TCR clonotypes and transcriptomes with a subset of intratumoral effector/effector memory T cells (T_Eff/EMs), indicating their developmental ontogeny. Furthermore, CXCL16 is highly produced by tumor cells and CXCR6^- T_Eff/EMs are the major subset preferentially egressing the tumor to form distant T_RMs. Functionally, releasing CXCR6 retention in the primary tumor amplifies tumor-derived T_RMs in the lung and leads to superior protection against metastases. This immunologic fortification suggests a potential strategy to prevent metastasis in clinical oncology.