Imiquimod is an agonist of Toll-like receptor 7 (TLR7) and TLR8 and is used clinically for the treatment of certain forms of skin cancer. In the Journal of Clinical Investigation, Sibilia and colleagues demonstrate that imiquimod can trigger tumor clearance through the stimulation of 'killer' plasmacytoid dendritic cells (pDCs). Short-term application of imiquimod results in dermal cell death but not in any obvious production of inflammatory cytokines in the skin. However, imiquimod triggers skin mast cells to release the chemokine CCL2, which recruits pDCs. Imiquimod mediates protection against tumor challenge and, unexpectedly, also works in the complete absence of any adaptive immunity or natural killer cells. Instead, imiquimod activates pDCs to express soluble cytotoxic factors such as TRAIL and granzyme B, which could directly kill tumor cells. The production and signaling of interferon-α in response to imiquimod is essential for the upregulation of pDC cytotoxic factors. Thus, pDCs are important in the direct elimination of tumors.

J. Clin. Invest. (1 February 2012) doi:10.1172/JCI61034