Despite the transformative impact of immune checkpoint inhibitors (ICI) in metastatic melanoma, durable responses remain limited. To define clinically actionable resistance mechanisms, we performed integrated profiling, combining transcriptomic/pathway enrichment analysis, spatial proteomics, and peripheral immune phenotyping in 35 stage III–IV patients stratified by treatment response (responders [R], n=22; non-responders [NR], n=13).
Resistance to ICI was associated with activation of oxidative phosphorylation (q=0.005), epithelial–mesenchymal transition (q=0.009), UV response (q=0.008) pathways, and leucine-sensing/transport programs, including LAT1 and SESN2 (p