STING抑制肺腺癌休眠转移的再激活

SCI

26 April 2023

STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma

（Nature, IF: 69.504）

Hu J, Sánchez-Rivera FJ, Wang Z, Johnson GN, Ho YJ, Ganesh K, Umeda S, Gan S, Mujal AM, Delconte RB, Hampton JP, Zhao H, Kottapalli S, de Stanchina E, Iacobuzio-Donahue CA, Pe'er D, Lowe SW, Sun JC, Massagué J. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma. Nature. 2023 Mar 29. doi: 10.1038/s41586-023-05880-5. Epub ahead of print. PMID: 36991128.

Corresponding Author：Joan Massagué,PhD,Memorial Sloan Kettering Cancer Center, New York, NY, USA.

e-mail:massaguj@mskcc.org

ABSTRACT 摘要  

Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fuctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1–6 .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 identifed 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 TGFβ. 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 efects 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.

转移通常是由播散的癌症细胞发展而来，这些细胞在原发肿瘤治疗成功后仍处于休眠状态。这些细胞在介于免疫逃避的静止状态和易于被免疫介导消除的增殖状态之间变化。对于重新唤醒的转移细胞的清除以及如何通过治疗激活这一过程以消除患者的残余病灶，我们知之甚少。这里，我们使用惰性肺腺癌转移的模型，来确定从休眠期间退出时，免疫反应的癌细胞固有决定因素。肿瘤内在免疫调节因子的遗传筛选证实了干扰素基因刺激因子（STING）途径作为转移爆发的抑制因子。STING的活性在重新进入细胞周期的转移祖细胞中增加，并在突破性转移中STING启动子和增强子的高甲基化时被抑制或在响应TGFβ而重新进入休眠的细胞中被染色质抑制。STING在自发转移的癌细胞中的表达可抑制其生长。用STING激动剂对小鼠进行全身治疗可消除休眠性转移，并以T细胞和自然杀伤细胞依赖的方式防止自发爆发，这些效果需要癌细胞的STING功能。因此，STING提供了一个针对休眠性转移进展的检查点，并为预防疾病复发提供了一种治疗上可行的策略。

打赏