We investigated the effect of small molecule inhibitor of TP53 mutation (APR-246) in combination with decitabine on the proliferation of MDS/AML cells (SKM-1, NB4 and KASUMI-1) which carries the recurrent homozygous TP53 mutation p.R248Q (TP53 p.248Q)….We found DAC combined with APR-246 had a synergistic effect on tumor cells with TP53 p.248Q mutation in vitro....DAC activated a series of endogenous retroviruses (ERV) and upregulated TLR3 which activated anti-tumor immunity by promoting IFN-α secretion. However, IKK phosphorylation was also increased and induced NF-κB activation. Interestingly, this side-effect can be suppressed by APR-246, thereby synergistically promoting apoptosis of tumor cells.