Tumors (red) are attacked by surrounding mDCs (blue) and infiltrating pDCs (green).

Cytotoxic T cells that are trained by dendritic cells (DCs) to recognize tumor antigens are thought to be the main artillery in an antitumor response. But Stary et al. now find that the teachers can also be dangerous. On page 1441, the authors report that DCs are also loaded with cytotoxic proteins and thus act as weapons of tumor mass destruction.

Skin tumors known as basal cell carcinomas shrink when smeared with Imiquimod, a drug that activates Toll-like receptors (TLRs) 7 and 8 on DCs. Stary et al. had previously found that mouse tumors that responded best to these drugs contained a large number of DCs. And as DCs recruit and activate T cells, the team assumed that the drug instigated the DCs to call in T cell troops.

The new study, however, shows that DCs that are activated by TLR 7/8 work by an entirely new mechanism. In human carcinomas treated with Imiquimod, two DC subsets—myeloid DCs (mDCs) and plasmacytoid DCs (pDCs)—vastly outnumbered T cells. The mDCs surrounded the tumor mass, whereas the pDCs infiltrated it. They both expressed several cytolytic molecules.

The mDCs, like natural killer cells, killed tumor cells that did not express MHC class I. The pDCs acted more like T cells and specifically destroyed antigen-positive cells in vitro. This varied target specificity implies that, together, these DCs kill all kinds of tumor cells. Imiquimod may thus be useful to treat tumors that don't respond to T cell therapies.