Specific activation of toll-Like Receptor 9 (TLR9) by ligand CpG DNA/ODN can initiate downstream signaling.The activation of TLR9 signaling is regulated by Granulin,high-mobility group box-1 (HMGB1) and soluble TLR9.Interestingly,TLR9 is no longer only presented in the immune cells,but also expressed in many kinds of tumor cells.TLR9 is involved inmaintaining and promoting the malignant biological behaviors of tumor cells.Elucidation of the function of TLR9 inherent signaling pathways in the tumor cells will provide a novel idea for oncotherapy.