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 (T_RM)-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⁺ T_RM-like fate, establishing active immunosurveillance within nascent lesions. T_RM-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 T_RM-like cells and restraining both cytotoxic and sentinel functions. Tumor-site-specific Treg depletion reactivated T_RM-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.