Collectively, our results revealed that HDAC8 is a key protein involved in determining the sensitivity of ccRCC to TKIs; it mediates this effect by deacetylating ETS1 at the K245 site and promoting the interaction between ETS1 and HIF‐2α and enhancing the function of this complex. This evidence concerns the gene EPAS1 and nonpapillary renal cell carcinoma.