Our current findings address this knowledge gap and the central findings from our current work are: (1) Autophagy helps protect colon cancer stem cells against 5-FU treatment by modulating the GSK-3β/Wnt/β-catenin signaling; and (2) targeting VPS34/PIK3C3 can effectively kill the autophagy-high CSCs to promote efficacy of colon cancer therapies. The gene discussed is PIK3C3; the disease is malignant colon neoplasm.