Role of Cellular Senescence in Melanoma: Implications for Tumor Progression and Therapy

Aging is the most significant risk factor for cancer, with melanoma incidence and mortality rising with advancing age. Cellular senescence, a hallmark of aging, plays dual roles in melanoma progression, exerting both tumor-suppressive and tumor-promoting effects via the senescence-associated secretory phenotype (SASP) and its complex influence on the tumor microenvironment (TME).

Relevant literature was retrieved from PubMed, Web of Science, and Scopus from 2002 up to June 2025, using keywords related to melanoma, cellular senescence, SASP, senolytics, and immunotherapy. Studies were evaluated for mechanistic insights, preclinical evidence, and translational relevance.

Evidence indicates that senescent cells in melanoma can suppress tumor growth through cell cycle arrest and immune activation, yet also promote immune evasion, metastasis, and therapy resistance through SASP-mediated pathways. Traditional and targeted therapies can induce senescence, while senolytic agents, particularly in combination with immune checkpoint inhibitors, show promise in eliminating therapy-induced senescent cells and enhancing anti-tumor immunity in preclinical models.

The therapeutic potential of senescence modulation in melanoma is tempered by key challenges, including the pronounced heterogeneity of senescent cells, SASP's context-dependent effects, and limited melanoma- specific clinical trial data. Strategies to overcome these hurdles include biomarker-driven patient selection, senomorphic modulation, and rational senolytic-immunotherapy combinations.

Senescence-targeting strategies hold considerable promise for melanoma treatment but require deeper mechanistic characterization and robust early-phase clinical evaluation before routine clinical application. Integrating senescence modulation into precision oncology frameworks may ultimately improve outcomes in melanoma patients.