Both DCs and macrophages in the tumor microenvironment are known to promote immune tolerance 11 , 17 . Our previous work demonstrated that Stat3 is persistently-activated in myeloid cells in the tumor milieu and that genetic ablation of Stat3 in the myeloid compartment elicits potent antitumor immunity 10 . Furthermore, both CpG and LPS treatment activates Stat3 38 , 25 , 40 , which acts as a negative feedback mechanism to constrain Th1 immune responses. Therefore, we assessed whether the CpG-Stat3-siRNA conjugates could reverse the immunosuppressive effects imposed by the tumor-microenvironment and at the same time allow effective antitumor immunity induced by TLR9 triggering. Local treatment with CpG-Stat3 siRNA oligonucleotides inhibited growth of subcutaneously growing B16 melanoma (3-5 mm in diameter at the initial treatment). In contrast, treatment with unconjugated CpG-ODN plus Stat3 siRNA, or CpG-scrambled RNA construct, or GpC-Stat3 siRNA had significantly less antitumor effects (Fig. 4a) . The antitumor effects of CpG-Stat3 siRNA were confirmed by using two alternative Stat3 siRNA sequences (data not shown). To directly show that the antitumor effects induced by CpG-Stat3 siRNA were mainly mediated by immune cells, we performed in vivo experiments with antibodymediated depletion of CD8/CD4 T cells and NK cells. Without CD8 + and CD4 + immune cell populations (possibly also the cross-priming CD11c + CD8 + DCs), the effects of CpG-Stat3 siRNA treatment were partially reduced (Fig. 4b) . The therapeutic effects of CpG-Stat3 siRNA were abrogated in the absence of NK cells (Fig. 4b) .