Spatial tumour-immune ecosystems shape the efficacy of anti-PD1 immunotherapy in primary cutaneous melanoma

Intra-tumoral heterogeneity in melanoma arises from dynamic cancer cell plasticity and underlies various mechanisms of immune escape. Here, we combined high-plex immunofluorescence imaging with spatially resolved transcriptomics to map the architecture of melanoma cell states and their interactions with the immune microenvironment in primary cutaneous tumours prior to adjuvant anti-PD1 immune checkpoint inhibitor (ICI) treatment. Computational analyses showed that melanoma cells organise into spatially restricted patches, with a preferential organisation of undifferentiated cells associated with poor ICI efficacy. Neighbouring immune cell composition varied according to cancer cell states, with a crucial involvement of specific subsets of tumour-associated macrophages, driven by signalling pathways involving tumour-derived and microenvironmental cues such as IFN-γ and hypoxia. Integrated spatial analyses further revealed tumour-immune ecosystems that stratify patient outcomes, delineating configurations either associated with ICI efficacy or metastatic relapse. These results uncover the spatial landscape of tumour ecosystems and identify signalling pathways as potential targets for improving the efficacy of ICI in melanoma.