In this study, we illustrates that SMAD4 expression is downregulated in human NK cells within the CRC TME, and overexpression of SMAD4 enhance the cytotoxic ability of NK cells through upregulating the expression of the m6A reader protein YTHDF2 and promotes the expression of the NK activating receptor NKG2D. Here, YTHDF2 is linked to colorectal carcinoma.