ArticleCureus2026
Candidate MicroRNA Regulatory Axes in Melanoma CD8+ T Cell Exhaustion: A Network-Based In Silico Stratification.
Article in Cureus, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background Anti-programmed cell death protein-1 (anti-PD-1) immunotherapy has transformed the treatment of advanced melanoma, but durable benefit remains limited to a subset of patients. CD8+ T cell exhaustion contributes to immune escape in the melanoma tumor microenvironment, while the post-transcriptional regulation of exhaustion-associated genes by microRNAs (miRNAs) remains incompletely understood. Objective We characterized miRNA-mRNA regulatory associations in CD8+ T cell exhaustion-enriched melanoma transcriptomes, classified inverse associations as loss-of-repression (LoR) or active suppression (AS), extended the network to candidate long non-coding RNA (lncRNA)-miRNA-mRNA relationships, and examined whether network-derived transcriptomic scores were associated with anti-PD-1 outcomes in independent cohorts. Methods The TCGA-SKCM bulk transcriptomes were filtered by single-sample gene set enrichment analysis (ssGSEA), yielding 121 CD8+ T cell exhaustion-enriched cases and 115 cases with paired miRNA and mRNA measurements. Differentially expressed miRNAs (DEmiRNAs) were identified between fixed high- and low-exhaustion tertiles (n = 38 each) using two-sided Mann-Whitney U tests with Benjamini-Hochberg correction (|log₂FC| ≥ 0.5; false discovery rate (FDR) ≤ 0.05). Database-supported inverse Spearman's correlations (ρ ≤ -0.30; FDR ≤ 0.05) were assembled into a bipartite network. Edges were classified as LoR or AS, and a competing endogenous RNA (ceRNA) extension incorporated DIANA-LncBase/ENCORI lncRNA-miRNA interactions. Nine biologically anchored axes underwent continuous-score analysis and HC3 regression adjusted for tumor purity, CD8, fibroblast/CAF, myeloid, interferon-gamma, and sample type, together with four sensitivity analyses. Exploratory clinical testing used GSE78220 and the pre-PD-1 biopsy subset of the DFCI melanoma cohort (cBioPortal study identifier: mel_dfci_2019). Results Twenty-six DEmiRNAs (20 upregulated and 6 downregulated) formed 326 inverse miRNA-mRNA edges, comprising 263 AS and 63 LoR associations. Six of nine focused axes met the adjusted-support criterion, and all six were AS-classified including upregulated miR-155-5p as the dominant hub, with inverse associations involving FOXO3 (
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