The immune system can serve as extrinsic tumor suppressor 7 , 8 , 9 . However, the tumor microenvironment is characterized by lack of tumor-specific CD8 + T cells and an excess of regulatory T cells and myeloid-derived suppressor cells (MDSC) that promote tumor immune evasion 10 , 11 . Myeloid cells and other immune cells in the tumor microenvironment also produce growth factors and angiogenic/metastatic factors critical for tumor progression 12 . The orchestration of these processes in the tumor microenvironment appears to be highly dependent on the oncogenic transcription factor, Stat3 13 , 14 , 15 , 16 , 17 . In particular, we and others have recently demonstrated a role of Stat3 in mediating tumor immune evasion 18 , 10 , 17 . Activated Stat3 in myeloid cells inhibits expression of a large number of immunostimulatory molecules related to Th1-type responses, while promoting production of several key immunosuppressive factors 17 , 19 , 20 as well as angiogenic factors 12 . In addition, by mediating signaling of certain cytokines and growth factors, notably IL-6, Stat3 activation in myeloid cells activates Stat3 in tumor cells, enhancing tumor cell proliferation and survival 21 -24 . Because Stat3 also restrains TLR-mediated Th1 immune responses 10 , 25 , 17 , we reasoned that simultaneously silencing Stat3 by siRNA and triggering TLRs by their agonists could effectively shift the tumor microenvironment from prooncogenic to anti-tumor. A recent study using polymer-mediated in vivo transfection of 5′triphophate-Bcl2 siRNA has demonstrated the benefits of simultaneously inducing antitumor immunity and silencing a pro-oncogenic gene 4 .