The clinical relevance of targeting CSCs is supported by recent studies, including CD24 targeting for the treatment of pancreatic and colon,69 CD44 targeting for the treatment of acute myeloid leukemia70 and CD133 targeting for gastric and hepatocellular cancer.71 In conclusion, our data here and from our previous studies21 indicate that an alternative therapeutic strategy for eradication of ccRCC would be to promote CSCs survival by a TNFR2 selective agonist in combination with cell‐cycle dependent cytotoxic drugs. This evidence concerns the gene CD44 and hepatocellular carcinoma.