Background <p>Recent advances in melanoma treatment, including targeted therapies and immunotherapies, have improved patient outcomes. The discovery of molecular targets is crucial, enabling more precise treatment strategies that address specific genetic mutations. Our study delves into the multifunctional role of coagulation factor Coagulation Factor V (F5) in melanoma.</p> Methods <p>The melanoma data about gene expression, clinical information, prognosis, and immune infiltration were obtained from TCGA database. The A2058 cell were used to examine the effects of F5 in the behavior of tumor cells in vitro.</p> Results <p>Our results revealed that F5 expression levels in melanoma patients are significantly correlated with prognosis, with lower expression levels associated with poorer outcomes. Single-cell transcriptomic analysis further revealed a strong association between F5 expression and diverse immune cell populations and chemokines. In addition, overexpression of F5 in the melanoma cell line A2058 significantly inhibited cell migration, proliferation, and colony formation capacity, while upregulating the expression of multiple immune chemokines.</p> Conclusions <p>These findings go beyond the traditional view of F5 as a coagulation factor and reveal its importance in immunomodulation and tumor biology.</p>