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.

在原发性肿瘤看似成功得到治疗后，仍有播散性癌细胞隐匿于远处器官内，此类细胞常引发转移性复发。播散性癌细胞在免疫逃逸的静息状态与细胞周期再进入状态之间动态切换，这使其易被免疫系统清除1-6。目前对于决定免疫清除觉醒转移性癌细胞的分子机制，以及如何通过治疗激活该过程以清除患者体内残留播散性病灶的相关认知仍十分有限。本研究采用惰性转移模型，旨在探究癌细胞从静息状态退出过程中，癌细胞固有免疫反应性的决定因素。通过对肿瘤固有免疫调控因子开展体内遗传筛选，我们在人类与小鼠肺腺癌转移的静息模型中，鉴定出STING（stimulator of interferon genes，干扰素基因刺激因子）通路是转移性暴发的主要抑制因子。进入细胞周期的转移前体细胞中，STING蛋白水平与信号通路活性均会升高，而在显性转移灶中，该通路则因表观遗传沉默而受到抑制。从转移性暴发灶中分离得到的侵袭性癌细胞，若诱导其STING信号通路激活，则可通过依赖T细胞与自然杀伤（NK）细胞的方式抑制转移进程。采用药理学STING激动剂对小鼠进行全身给药，可清除惰性转移性癌细胞并阻止自发性转移发生。综上，STING信号通路可作为抑制静息转移性疾病进展的检查点，同时为预防疾病复发提供了可转化的治疗策略。