We confirmed that local treatment with CpG-Stat3 siRNA can reduce growth of other tumors independently of their genetic background. CpG-Stat3 siRNA oligonucleotides inhibited growth of both a poorly immunogenic variant of K1735 melanoma, C4 41 , and CT26 colon carcinomas in C3H and BALB/c mice, respectively (Fig. 4c,d) . Furthermore, CpG-Stat3 siRNA treatment of the carcinoembryonic antigen (CEA) transgenic C57BL/6 mice bearing MC38 colon carcinomas expressing CEA led to tumor regression in some mice (Fig. 4e) . To assess in vivo effects of the CpG-Stat3 siRNA on tumor cells, we stained B16 tumor tissues with fluorescent antibody specific to activated caspase-3. Data from these analysis showed that B16 tumors received CpG-Stat3 siRNA had undergone more extensive apoptosis relative to the other three treatment groups ( Supplementary Fig. 11 ). We also investigated the possibility that CpG-Stat3 siRNA could be systemically delivered to achieve gene silencing and antitumor effects. Intravenous injection (i.v.) of CpG-Stat3 siRNA (0.78 nmol) reduced Stat3 expression in DCs within TDLNs relative to CpGscrambled RNA (Fig. 4f) . Systemic delivery of CpG-Stat3 siRNA to inhibit metastasis was tested in an experimental B16 lung metastasis model. Relatively small amounts of the oligonucleotide (< 1 mg/kg) were used for the systemic injection, which led to significant reduction in the number of lung metastasis (Fig. 4g) . Lower antitumor effect due to CpGscrambled RNA and CpG ODN alone was also observed. Thus, maximal antitumor effects required conjugation of the CpG TLR9 ligand with a functional Stat3 siRNA.