Genotype-driven tumor ecosystems drive immune evasion and immunotherapy resistance in melanoma.

backgroundGenetic and transcriptional alterations in cancer cells shape their interactions with immune and stromal compartments, thereby influencing tumor progression, immune evasion, and response to immune checkpoint inhibitors (ICIs). Yet, how these interactions are spatially organized within melanoma and how they relate to clinical outcome remains incompletely understood.

methodsWe used spatial multi-omic profiling on melanoma tissues from patients, compared those with loss-of-function mutations in the Neurofibromin 1 (NF1) tumor suppressor gene to those with intact NF1, and integrated these results with functional studies and subsequent gene expression changes observed in patient-derived melanoma models and an immunotherapy-resistant syngeneic mouse model.

resultsSpatial multi-omic analysis of melanoma tissues from patients identified 12 meta-niches composed of distinct cell populations with unique molecular features. Although all tumors contained these meta-niches, those enriched in immunosuppressive cancer-associated fibroblasts (CAFs) and macrophages were significantly more common in tumors with NF1 loss. Conversely, niches enriched in cytotoxic CD8

conclusionsThese findings define spatially organized, functionally distinct meta-niches enriched in NF1-mutant melanoma that may contribute to their aggressive disease features and poor ICI response. Our study links an understudied melanoma driver to specific immune-evasion mechanisms and identifies EGFR inhibition as a candidate strategy to improve outcomes in patients with NF1-mutant melanoma resistant to immunotherapy.