Nonresponders to PD-1 therapy share a combined OXPHOS and neuronal-like resistance program in melanoma

BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting PD-1 have transformed melanoma therapy, yet only a subset of patients derive durable benefit. The molecular programs underlying responsiveness remain incompletely defined. We aimed to identify gene-expression patterns that distinguish responders from nonresponders by focusing on alterations specifically related to transformed cancer hallmarks. METHODS: We compiled pretreatment transcriptional profiles from 17 independent studies, pooling data for 551 melanoma patients, including 233 responders to anti-PD-1 therapy. ROC analyses evaluated the discriminative potential of individual genes. Genes with high AUC and expression values in both responders and nonresponders were identified. Hallmark enrichment was assessed using cancerhallmarks.com, and gene ontology analyses were conducted to characterize the underlying biological programs. Significant differences were based on a fold change ≥ 1.4 and a p<0.05. RESULTS: In responders, 467 overexpressed genes revealed a highly coordinated immune-inflamed state, with enriched Fc-gamma receptor signaling (p = 3.97×10⁻⁸²), classical complement activation (p = 1.42×10⁻⁸¹), and T- and B-cell receptor signaling (p = 3.47×10⁻⁴, 3.06×10⁻⁴). GO terms highlighted T-cell activation, lymphocyte-mediated immunity, and a strong IFN-gamma response. Cancer hallmark enrichment analysis identified “Evasion of Immune Destruction” as the only significant hallmark (p < 0.0001), emphasizing that clinical benefit arises from a pre-existing immune-activated microenvironment rather than tumor-intrinsic programs, such as proliferation, metabolic rewiring, or differentiation state. The 685 overexpressed genes in nonresponders converged on a metabolically amplified and lineage-rewired tumor state. Reactome analysis revealed a strong upregulation of mitochondrial programs, including mitochondrial RNA processing (p = 1.47 × 10⁻¹²) and respiratory electron transport (p = 2.92 × 10⁻²), defining a high-OXPHOS phenotype that can suppress antitumor immunity. Complementary GO terms related to myelination, oligodendrocyte differentiation, and trans-synaptic signaling highlighted a neuronal-like dedifferentiation program linked to reduced antigen presentation and T-cell exclusion, creating a multilayered barrier to immune recognition. CONCLUSION: ICI nonresponders consistently exhibit high-OXPHOS metabolism and neuronal-like dedifferentiation, resulting in immune silence. The co-occurrence of these two resistance programs across multiple independent cohorts reveals a combined transcriptional barrier to PD-1 response.