How cancer cells make and respond to interferon-I

Acute exposure of cancer cells to high concentrations of type I interferon (IFN-I) drives growth arrest and apoptosis, whereas chronic exposure to low concen-trations provides important prosurvival advantages. Tyrosine-phosphorylated IFN-stimulated gene (ISG) factor 3 (ISGF3) drives acute deleterious responses to IFN-I, whereas unphosphorylated (U-)ISGF3, lacking tyrosine phosphoryla-tion, drives essential constitutive prosurvival mechanisms. Surprisingly, pro-grammed cell death-ligand 1 (PD-L1), often expressed on the surfaces of tumor cells and well recognized for its importance in inactivating cytotoxic T cells, also has important cell-intrinsic protumor activities, including dampening acute responses to cytotoxic high levels of IFN-I and sustaining the expression of the low levels that benefit tumors. More thorough understanding of the newly recognized complex roles of IFN-I in cancer may lead to the identification of novel therapeutic strategies.

Automated summary

Acute exposure to high concentrations of IFN-I leads to growth arrest and apoptosis in cancer cells, while chronic exposure to low concentrations provides prosurvival advantages. Phosphorylated ISGF3 drives acute deleterious responses to IFN-I, while unphosphorylated ISGF3 drives essential constitutive prosurvival mechanisms. PD-L1, known for its role in inactivating cytotoxic T cells, also has cell-intrinsic protumor activities, including dampening acute responses to high levels of IFN-I and sustaining expression at low levels that benefit tumors. Understanding the complex roles of IFN-I in cancer may lead to new therapeutic strategies.