Transcriptomic analysis of tissue-resident memory T cells of the fallopian tube reveals a precursor immune surveillance network for ovarian cancer prevention.

The fallopian tube (FT) is increasingly recognized as the origin of high-grade serous ovarian cancer (HGSOC), yet its immune landscape remains poorly understood. Here, we employ single-cell RNA sequencing and paired T-cell receptor sequencing to profile tissue-resident memory-like T cells (TRML) from patient-derived matched non-cancerous FT, metastatic tumors, and peripheral blood. We identify substantial clonal and functional overlap (18.4%) between FT-derived and tumor-infiltrating TRMLs, exceeding that of circulating T cells. Shared clonotypes are preferentially enriched in exhausted CD8+ subsets, including a previously uncharacterized SIK3-high subset linked to epigenetic plasticity and metabolic adaptation. Functionally, FT-derived TRMLs recognize autologous tumor antigens, showing strong interferon-γ (IFN-γ) responses and CD137 upregulation in organoid coculture assays, supporting a role in early immune surveillance. Notably, FT TRMLs exhibit lower exhaustion than tumor counterparts, suggesting therapeutic potential. These findings reveal a precursor immune surveillance network in the FT and support leveraging FT-resident T cells for cancer immunotherapy and prevention.