STING suppresses the reactivation of dormant metastasis

Metastatic relapse frequently develops from disseminated cancer cells that remain dormant in distant organs after the apparently successful treatment of a primary tumor. Disseminated cancer cells fluctuate between immune evasive quiescent and cell cycle reentry states, which exposes them to elimination by the immune system1-6. Little is known about the molecules that determine immune-mediated clearing of awakened metastatic cells and how this process could be therapeutically activated to eliminate residual disseminated disease in patients. Here, we use models of indolent metastasis to identify cancer cell-intrinsic determinants of immune reactivity during cancer cell exit from dormancy. Through in vivo genetic screens of tumor-intrinsic immune regulators, we identified the STING (stimulator of interferon genes) pathway as a major suppressor of metastatic outbreak in dormant models of human and mouse lung adenocarcinoma metastasis. STING levels and signaling activity rise in metastatic progenitors that enter the cell cycle and are dampened by epigenetic silencing in overt metastases. Induction of STING signaling in aggressive cancer cells derived from metastatic outbreaks suppresses metastasis in a T cell and NK cell-dependent manner. Systemic treatment of mice with pharmacologic STING agonists eliminates indolent metastatic cells and prevents spontaneous metastasis. Thus, STING signaling represents a checkpoint against the progression of dormant metastasis and suggests a therapeutically actionable strategy for the prevention of disease relapse.