STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma

Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination(1-6). Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFb. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner-these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.

Automated summary

Metastasis often occurs when cancer cells that are dormant after primary tumor treatment become active again. The stimulator of interferon genes (STING) pathway has been identified as a suppressor of metastatic outbreak and a potential therapeutic target to prevent disease relapse. By understanding the determinants of immune reactivity during exit from dormancy, researchers have found that STING activity increases in metastatic progenitors that re-enter the cell cycle and can be dampened by methylation or chromatin repression. Activation of STING function in cancer cells derived from spontaneous metastases eliminates dormant metastasis and prevents spontaneous outbreaks.