Taken together, systemic ALK5 inhibition in melanoma-bearing mice blocks TGF-β signalling by not only inhibiting R-Smad phosphorylation, but also inducing ubiquitin-mediated degradation of Smad4 protein in immune cells, especially in CD8+ T cells, whereas ALK5 inhibition suppresses intact Smad4-mediated TGF-β signalling in B16 melanoma cells. This evidence concerns the gene SMAD4 and melanoma.