Deescalation of immunotherapy in metastatic melanoma patients with scheduled drug holidays

Results: Hierarchical clustering of 55 genes associated with PFS identified two molecular clusters.Cluster A demonstrated better PFS (median: 59.4 months) compared to Cluster B (median: 2.4 months, P = 0.0004).Multivariate Cox analysis confirmed that molecular clustering was an independent predictor of PFS (P < 0.001).Differential expression analysis revealed 113 DEGs, with Cluster B showing enrichment of cell cycle pathways and downregulation of immune-related pathways, including antigen presentation and IFN- signaling.xCell analysis revealed reduced levels of CD4+, CD8+, and Th1 populations in Cluster B. Mass cytometry identified specific PD-1+ T cell and T4 effector memory subpopulations associated with immunotherapy response (P < 0.05).Conclusions: This study offers valuable insights into the molecular and immune landscape shaping ICI response in advanced melanoma.Molecular profiling identified biomarkers of ICI response, including antigen presentation and IFN- signature, which surpass traditional clinical variables.Furthermore, circulating PD-1 + T cell subpopulations emerged as promising predictive biomarkers, providing a complementary tool for improved patient stratification and more informed therapeutic decision-making.