Cellular senescence in the photoaged skin microenvironment promotes early melanoma progression

Exposure to ultraviolet (UV) radiation and natural aging are the major risk factors for the development of cutaneous melanoma (CM), yet the mechanisms by which they foster a tumor-permissive skin microenvironment (ME) remain unclear. We show that aging and chronic exposure to UVB induced accumulation of cellular senescence, enhanced expression of the senescence-associated secretory phenotype (SASP), inflammation in the skin, and dermal remodeling leading to an immunosuppressive ME and accelerated melanoma growth. The secretome from UVB-induced senescent fibroblasts (SnDFbs) promoted melanoma cell proliferation, invasion, and migration in vitro. Co-implantation of melanoma cells with SnDFbs also enhanced tumor growth in vivo. Notably, elimination of UVB-induced senescent cells using senolytic drugs or a genetically engineered mouse model mitigated tumor progression and regulated the UVB-induced immunosuppressive microenvironment. Our findings highlight SnDFbs as key drivers of early melanoma progression and therefore as potential targets for early intervention strategies.