We previously reported that ligation of TNFR2 drives ccRCC‐CD133+CSCs proliferation and increases their sensitivity to cell cycle‐dependent cytotoxicity.21 Here we elucidate the mechanism of the growth‐promoting effect of TNFR2 signaling in CD133+CSCs in ccRCC using molecular, cellular, and imaging techniques. Here, PROM1 is linked to nonpapillary renal cell carcinoma.