Our present results reveal that TOX3 is particularly abundant in cCSCs and metastatic and recurrent tumor tissues from CRC patients and is essential for cCSCs evolution and drug resistance development by transcriptionally up-regulating ABCG2 via binding at ABCG2 promoter, which suggests that TOX3/ABCG2 signaling may represent a new layer of control for cancer initiation and progression, particularly for CRC, by reshaping cancer cell stem-like traits and drug resistance. Here, ABCG2 is linked to neoplasm.