Spatial architecture of the melanoma immune niche reveals CORO1A as a functional hub for T cell cytotoxicity and immunotherapy synergy

BACKGROUND: Immune checkpoint blockade (ICB) often fails in cutaneous melanoma due to an incomplete understanding of the spatially organized tumor microenvironment (TME). This study aims to define the spatial architecture of the melanoma TME and identify key molecular regulators that determine anti-tumor immunity and ICB response. METHODS: We employed an integrative analysis of single-cell and spatial transcriptomics to map the TME. We defined spatial domains and deconvoluted their cellular composition. Cell-cell communication and risk modeling were performed. Functional roles of candidate genes were assessed using in vitro co-culture with anti-PD-1 and in vivo knockdown in a humanized mouse model. RESULTS: We delineated two prognostically significant spatial domains: an Immune region and a Melanocyte region. Multi-omics convergence nominated CORO1A as a key regulator within the immune niche. Its knockdown synergized with anti-PD-1 to suppress tumor growth in vivo, and anti-PD-1 downregulated its expression in vitro. We further identified APP-CD74 and FN1-CD44 as key inter-domain communication axes. CONCLUSION: Our study provides a spatially resolved blueprint of the melanoma TME and identifies CORO1A as a functional regulator within the immune niche, where its modulation enhances T-cell activity and synergizes with ICB. These findings reveal spatial organization as a critical determinant of immunotherapy efficacy and nominate CORO1A as a promising target for combination therapy.