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

Background

Genetic 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.

Methods

We 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.

Results