Our results demonstrating that selective inhibition of SMAD3 or HDAC6-dependent SMAD3 bioavailability was more potent than Galunisertib (LY2157299) in inhibiting tumor growth and metastasis, combined with those indicating a significant increase in SMAD3 activation in the hypoxic tumor microenvironment, suggest that SMAD3 can be an interesting therapeutic target for impeding cancer progression. Here, SMAD3 is linked to neoplasm.