siRNA delivery not Toll-free

Activating the tumor-associated immune system with an siRNA conjugated to a Toll-like receptor 9 ligand is a promising anticancer strategy. The future of RNA interference (RNAi) as a therapeutic depends on hitting the right target in the appropriate tissue or cell type. Several ingenious strategies devised in the past few years have shown that gene-specific silencing by small interfering (si)RNAs can have therapeutic effects at least in preclinical models. In this issue of Nature Biotechnology, Yu and colleagues present a novel siRNA delivery approach targeting phagocytic cells that requires Toll-like receptor (TLR)9 activation. This strategy promotes cytokine production and effector cell activation in the tumor microenvironment, enhancing antitumor activity.