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MELANF\u03b1 (NCT03348891) is an open\u2010label, prospective, multicenter cohort of 60 patients with advanced melanoma receiving ICI (bitherapy: ipilimumab + nivolumab; monotherapy: pembrolizumab or nivolumab). The primary objective was to evaluate whether changes in plasma TNF between baseline (W0) and week 12 (W12) identified patients with non\u2010progressive disease at W12. Secondary and exploratory objectives were to assess the association between plasma TNF, tumor response, and changes in circulating T cells. Plasma TNF increased along therapy, but its W12\/W0 fold change was not associated with non\u2010progressive disease at W12. However, plasma TNF levels at W12 were significantly higher in non\u2010responders than in responders across therapies (<jats:italic>p<\/jats:italic>\u2009=\u2009.0129). The remodeling of circulating T cell subpopulations was mostly triggered by bitherapy. Increased proportions of circulating central memory and effector memory CD8 T cells after bitherapy were positively and negatively associated with response to treatment, respectively. In this cohort, circulating T cells from responders and non\u2010responders also displayed distinct molecular characteristics. Indeed, responders showed an increased proportion of CD8 T cells with low enrichment of TNF\u2010related pathways and high cytotoxic potential, while non\u2010responders displayed increased proportions of circulating CD8 EM T cells enriched for TNF\u2010related pathways and directed toward cytokine expression. In conclusion, our study shows that elevated plasma TNF and enriched TNF pathways in T cells are associated with poorer clinical outcomes, reinforcing the notion that TNF may dampen ICI efficacy.<\/jats:p>","DOI":"10.1002\/ijc.35416","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T03:40:58Z","timestamp":1742269258000},"page":"534-548","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>TNF<\/scp> signature in advanced melanoma patients treated with immune checkpoint inhibitors: Results from the <scp>MELANF\u03b1<\/scp> clinical study"],"prefix":"10.1002","volume":"157","author":[{"given":"Mathieu","family":"Virazels","sequence":"first","affiliation":[{"name":"Unit\u00e9 Mixte de Recherche INSERM 1037, CNRS 5071 Universit\u00e9 Toulouse III\u2014Paul Sabatier, Centre de Recherches en Canc\u00e9rologie de Toulouse (CRCT)  Toulouse France"},{"name":"Equipe Labellis\u00e9e 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