The small-molecule immune response modifier imiquimod--its mode of action and clinical use in the treatment of skin cancer.

Due to its good clinical efficacy against malignant skin tumours, the topical immune response modifier, imiquimod, has attracted much interest among researchers and clinicians alike. Imiquimod exerts its antitumoural effect, at least in part, through agonistic stimulation of TLR-7 and TLR-8 on dendritic cells, followed by NF-kappaB-dependent secretion of a multitude of pro-inflammatory cytokines. The net result of this pro-inflammatory activity is a profound tumour-directed cellular immune response. Recent research has revealed an additional mode of action inasmuch as imiquimod interferes with adenosine receptor signalling, even in TLR-7- and TLR-8-negative cells, thereby presumably augmenting inflammatory signalling cascades. Moreover, at higher concentrations imiquimod also exerts direct proapoptotic activity against tumour cells. This mode of action appears to be independent of membrane-bound death receptors but is mediated, at least in part, through Bcl-2-dependent release of mitochondrial cytochrome c and subsequent caspase activation. Overall, a combination of several complementary antitumoural modes of action appears to underlie the great utility of imiquimod for treating cutaneous tumours.