Tumors flip out from TNF injections. Unfortunately, bodies do too. Huys et al. discover that blocking type 1 interferons (IFNs) prevents TNF-induced shock but leaves its tumor-fighting activities intact.

Type 1 IFNs, such as IFN-β, are among the hordes of cytokines, enzymes, and adhesion molecules stimulated by TNF. Although type 1 IFNs are typically associated with fighting viruses, Huys and colleagues show that these cytokines also mediate TNF-induced shock. Mice lacking IFN-β or its receptor, IFNAR-1, survived a normally lethal injection of TNF, with decreased inflammatory cytokine production and less tissue damage and cell death in the liver and bowels. These data are consistent with prior reports showing that IFN-β– and IFNAR-1–deficient mice are resistant to endotoxic shock, which is mediated largely by TNF.

Based on gene expression profiles, TNF induced a large number of genes via IFNAR-1. Among them were those encoding chemokines that attract white blood cells. Indeed, fewer leukocytes infiltrated the livers of TNF-treated mice that lacked IFNAR-1.

Type 1 interferons, however, were not required for TNF's tumor-fighting skills. With or without IFNAR-1, tumors shrank after TNF treatment—a process thought to involve cell death in the tumor vasculature. The fact that mice lacking IFNAR-1 were spared the normally toxic side effects of TNF suggests therapeutic potential. However, the risk of virus infection must be carefully assessed before interferon blockers can be used alongside TNF treatment in cancer patients.