Mutation of tumor suppressor TP53 is the most common genetic alteration in human cancer, which not only compromises its anticancer activity, but also gains oncogenic function. Unlike other gene mutations, approximately 80% TP53 mutation is missense mutation, that a single-base alters in DNA and expresses full-length missense protein. These aberrant mutant p53 proteins not only loss their tumor suppressor activity but also exert a dominant-negative effect on wild-type p53, by forming hetero tetramers with them. The oncogenic functions of mutant p53 protein confer malignant transformation, and promote cancer stem cell behavior, invasiveness, metastasis and resistance to chemotherapy. Targeting mutant p53 has been a therapeutic strategy to improve cancer treatment, and it primarily focuses on reactivating the p53 functions by modifying mutant p53 protein conformations with small molecules. Understanding the molecular mechanism by which how cancer cells regulate mutant protein expression might discover novel approaches to target p53 mutants more effectively. Our study showed that the missense p53 R273H protein expression is regulated by the N6-methyladenosine (m6A). An m6A was identified by specific MeRIP qPCR at the mutant site of pre-mRNA in SW48/TP53-Dox colon cancer cells (TP53 R273H+/, introduced by CRISPR/Casp9 system). Silencing METTL3 (a methyltransferase for m6A) with siRNA or inhibition of methylation by neplanocin A (NPC) restored wild-type p53 protein and p53-responsive genes (p21, Puma, Bax), and resensitized SW48/TP53-Dox cells to anticancer drugs and induced apoptotic cell death and reduced cell proliferation. Further, we found that glycosphingolipid-enriched microdomains (GEMs) could modulate cSrc and beta-catenin pathway and upregulated the expression of METTL3 and m6A methylation of TP53 R273H. In addition to dysfunction in proliferation arrest and apoptosis, our further study indicates that, p53 missense mutation is involved in immune-tolerance to cancer. Transgenic mouse carrying a heterozygous p53R172H/+ (corresponding to human R173H) generated fewer natural killer (NK) cells in response to cancer cell invasion, and p53-mutant SVT breast cancer cells (TP53 G242A+/) could not promote NK activation either in co-culture or in mice. Since activation of NK cell via NKG2D ligands cause NK cell to secrete cytokines like IFN-gamma, we found an increased level of IFN-gamma in the co-culture of NK cells with EMT (WT p53) compared to SVT cells. Together, these studies have shown the GOF of p53 missense mutations in drug resistance and immuno-dysfunction of tumor rejection, and RNA m 6A methylation regulates mutant protein expression. Targeting m 6A methylation and glycosphingolipids might be an effective strategy to improve treatments of cancers carrying TP53 missense mutation.