Herein, we address this topic by implementing in a complementary manner experimental and in silico approaches, signifying that NRs to immunotherapy melanoma patients exhibit increased immune cell senescence in CD4+ and CD8+ T-cell, B-cell (CD19+/CD20+) and natural killer (NK) cell populations compared to Rs. In line with these findings, we showed for the first time that senescent T-cells demonstrate dysfunctional properties favoring immune suppression and resistance to immunotherapy. Here, CD4 is linked to melanoma.