A longitudinal, multi-omic atlas reveals the emergence of a spatially organized immunosuppressive ecosystem in resistant melanoma

Despite advances in immune checkpoint blockade, resistance in metastatic melanoma remains a major challenge. To decode resistance mechanisms, we generate a comprehensive longitudinal, multi-omic, and spatial atlas of 45 tumor samples across 10 patients. Analysis reveals resistant tumors undergo convergent evolution toward a shared, spatially organized immunosuppressive ecosystem. We identify a structural mechanism characterized by spatial partitioning of immune checkpoints, where B7-H3 dominates MITF-high niches while IDO1 characterizes MITF-low zones. Furthermore, integrated single-cell and spatial analysis identifies a specific malignant subclone (c1) and a distinct architectural niche (RCN3), both exhibiting aberrant PI3K-mTOR signaling. Notably, c1 promotes the "ignored tumor" phenotype via FN1-ITGB1 and GDF15 signaling. Validated across independent cohorts, these spatial and molecular signatures predict poor survival and point to actionable targets. Ultimately, our study elucidates the spatial logic of resistance and provides a rationale for translating multi-omic discoveries into actionable, personalized therapeutic strategies.