Abstract
BACKGROUND: Melanoma is one of the most immunogenic malignancies, yet resistance to immune checkpoint inhibitors (ICIs) remains a major obstacle to durable therapeutic success. Emerging evidence indicates that aging-related processes, including cellular senescence and immunosenescence, can reshape the tumor microenvironment (TME) to favor immune evasion and disease progression. Senescent melanoma and stromal cells secrete a senescence-associated secretory phenotype (SASP) that alters immune cell recruitment and function, while immunosenescence leads to diminished cytotoxic responses and the accumulation of dysfunctional or suppressive immune subsets. AIM: This review explores the interplay between cellular senescence and immunosenescence in melanoma, highlighting their contributions to tumor progression and immunotherapy resistance, and discusses potential strategies to therapeutically target senescence-related pathways. METHODS: A systematic review of studies published between 2000 and 2024 was performed using PubMed, Web of Science, and Scopus. Literature included mechanistic investigations of senescence in melanoma, analyses of immunosenescence in cancer patients, and preclinical or translational studies targeting senescence-related pathways. RESULTS AND CONCLUSIONS: Senescent tumor and stromal cells drive a pro-inflammatory and immunosuppressive TME through SASP, while aging immune cells exhibit impaired antigen presentation, reduced cytotoxicity, and increased suppressive subsets. These dual processes form a self-reinforcing cycle of chronic inflammation and immune dysfunction, ultimately undermining the efficacy of ICIs. Targeting senescence, through senolytics, senostatics, or SASP modulators, has shown promise in preclinical models and may restore immune competence in melanoma. However, clinical translation requires further investigation to validate safety and efficacy. Addressing both cellular and immune senescence represents a novel and promising direction to overcome therapeutic resistance and improve melanoma outcomes.