Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Sci Adv. 2020 Jun 12;6(24):eaba7589. doi: 10.1126/sciadv.aba7589. eCollection 2020 Jun.
The stimulator of interferon (IFN) genes (STING) pathway constitutes a highly important part of immune responses against various cancers and infections. Consequently, administration of STING agonists such as cyclic GMP-AMP (cGAMP) has been identified as a promising approach to target these diseases. In cancer cells, STING signaling is frequently impaired by epigenetic silencing of STING; hence, conventional delivery of only its agonist cGAMP may be insufficient to trigger STING signaling. In this work, while expression of STING lacking the transmembrane (TM) domain is known to be unresponsive to STING agonists and is dominant negative when coexpressed with the full-length STING inside cells, we observed that the recombinant TM-deficient STING protein complexed with cGAMP could effectively trigger STING signaling when delivered in vitro and in vivo, including in STING-deficient cell lines. Thus, this bioinspired method using TM-deficient STING may present a universally applicable platform for cGAMP delivery.
干扰素（IFN）基因刺激物（STING）通路是针对各种癌症和感染的免疫反应的一个非常重要的部分。因此，STING 激动剂（如环鸟苷酸-腺苷酸（cGAMP））的给药已被确定为靶向这些疾病的一种很有前途的方法。在癌细胞中，STING 信号经常被 STING 的表观遗传沉默所抑制；因此，仅传递其激动剂 cGAMP 可能不足以触发 STING 信号。在这项工作中，虽然已知缺乏跨膜（TM）结构域的 STING 对 STING 激动剂无反应，并且在与全长 STING 在细胞内共表达时表现为显性负性，但我们观察到与 cGAMP 复合的重组 TM 缺失 STING 蛋白复合物在体外和体内，包括在 STING 缺失的细胞系中，都能有效地触发 STING 信号。因此，这种使用 TM 缺失 STING 的仿生方法可能为 cGAMP 的传递提供了一个普遍适用的平台。
