The initial melanoma T cell infiltrate is defined by tissue-resident programs restrained by regulatory T cells

How the immune system surveys nascent tumors and how this surveillance is subverted remain poorly understood. Using high-plex cyclic immunofluorescence and 3D imaging, we identified regulatory T (Treg) cells that co-localize with tissue-resident memory (TRM)-like T cells in early-stage human melanoma. In an autochthonous Braf/PTEN melanoma model expressing a defined tumor antigen, the initial CD8+ T cell infiltrate adopts a CD103+CD101+ TRM-like fate, establishing active immunosurveillance within nascent lesions. TRM-like cells dominate early tumors, occupy a stable epidermal niche, express effector molecules, and initiate T cell recruitment. However, Treg cells adopt a parallel tissue-resident phenotype, co-localizing with TRM-like cells and restraining both cytotoxic and sentinel functions. Tumor-site-specific Treg depletion reactivated TRM-like cells, drove robust T cell recruitment, expanded tumor-specific responses, and limited tumor growth. These findings reveal how early immunosurveillance is established through tissue-resident programs and identify Treg co-option of this response as a critical mechanism of tumor immune evasion. One Sentence SummaryNascent melanoma imprints a tissue-resident program on the initial CD8+ T cell infiltrate, which is suppressed by regulatory T cells as a critical checkpoint in immune evasion.