Melanoma, an aggressive neoplasm with a propensity for metastasis, remains challenging to treat because of its rapid progression, high heterogeneity, and resistance to conventional chemotherapeutic agents. In this context, tissue inhibitor of metalloproteinases-3 (TIMP-3) has been shown to exert multifaceted anti-tumor activities through the induction of apoptosis, inhibition of matrix metalloproteinases (MMPs), suppression of angiogenesis, and a marked reduction in melanoma invasiveness, thereby representing a promising molecular target for therapeutic intervention. Previous studies have demonstrated that adenoviral-mediated delivery of TIMP-3 can effectively inhibit tumor formation and growth in vivo through mechanisms that include stabilization of death receptors, thereby sensitizing melanoma cells to apoptotic signals and impairing angiogenesis.