Chronic type II interferon promotes tumor growth via type I interferon-mediated prostaglandin synthesis [RNA-seq]

Paradoxically, interferon signaling can also activate anti-inflammatory16 mechanisms that allow cancer cells to evade the immune system. We sought to determine how chronic interferon affects cancer cell metabolism and whether these changes contribute to a switch from anti-tumorigenic to pro-tumorigenic interfon activity.

We found that chronic type II interferon (IFN-II) exposure uniquely affected mitochondrial electron transport chain activity,20 rewired the TCA cycle, and upregulated eicosanoid production. Furthermore, it caused a type I interferon (IFN-I) response mediated by mitochondrial RNA release that synergized with IFN-II to enhance tumor growth via increased immunosuppressive prostaglandin E₂ synthesis. This covert IFN-prostaglandin pathway could be an actionable therapeutic target to reduce tumor growth24 and/or combat immunotherapy resistance.