SMAD4 also plays a vital role in regulating the immune microenvironment of CRC, including influencing macrophage polarization of macrophages,51,52 and the function of natural killer cells, dendritic cells, and T cells.53 Loss of SMAD4 may induce immune cells to adopt a pro-tumorigenic phenotype, thus worsening patient prognosis.54,55. Here, SMAD4 is linked to colorectal carcinoma.