A STAT3–STING–IFN axis controls the metastatic spread of small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by a high metastatic potential with an overall survival rate of ~5%. The transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed by >50% of tumors, including SCLC, but its role in SCLC development and metastasis is unclear. Here, we show that, while STAT3 deletion restricts primary tumor growth, it paradoxically enhances metastatic spread by promoting immune evasion. This occurs because STAT3 is crucial for maintaining the immune sensor stimulator of interferon (IFN) genes (STING). Without STAT3, the cyclic adenosine monophosphate–guanosine monophosphate synthase–STING pathway is inactive, resulting in decreased type I IFN secretion and an IFN gene signature. Importantly, restoration of IFN signaling through re-expression of endogenous STING, enforced expression of IFN response factor 7 or administration of recombinant type I IFN re-established antitumor immunity, inhibiting metastatic SCLC in vivo. These data show the potential of augmenting the innate immune response to block metastatic SCLC. Here, the authors show that signal transducer and activator of transcription 3 (STAT3) has dual functions in small cell lung cancer as its deletion inhibited primary tumor growth but boosted metastatic spread. These seemingly opposing functions are a result of the requirement of STAT3 for stimulator of interferon genes–interferon signaling in metastasis and the authors show how it can be targeted in mice.