SMAD4 and colorectal carcinoma: Studies have shown that, the expression of SMAD4 is significantly reduced or completely absent in CRC.31,32 This dysregulation not only weakens the function of SMAD4 in inhibiting tumor cell proliferation, invasion, and metastasis but also may lead to the deterioration of the tumor microenvironment, thereby promoting tumor metastasis and the emergence of drug resistance.