By using a SIS3 that specifically inhibits phosphorylation, DNA binding and protein interaction of Smad329, we demonstrated that systemic treatment with SIS3 (2.5, 5, 10 μg g−1, intraperitoneal (i.p.), daily) successfully blocked the Smad3 activation in the tumour microenvironment and significantly suppressed the tumour growth and invasion and associated with a 100% overall survival rate in the B16F10 and LLC tumour-bearing Smad3+/+ mice. This evidence concerns the gene SMAD3 and neoplasm.