Fukuda Keitaro
RIKEN Center for Integrative Medical Sciences (IMS), Laboratory for Skin Homeostasis, Yokohama 230-0045, Japan.
Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Cancers (Basel). 2023 Apr 1;15(7):2114. doi: 10.3390/cancers15072114.
cGAS and AIM2 are CDSs that are activated in the presence of cytosolic dsDNA and are expressed in various cell types, including immune and tumor cells. The recognition of tumor-derived dsDNA by CDSs in the cytosol of tumor-infiltrating dendritic cells (TIDCs) activates the innate and acquired immunity, thereby enhancing anti-tumor immune responses. STING is the downstream signaling effector of cGAS that induces type I interferon (IFN) signaling. Owing to their ability to activate TIDCs, STING agonists have been intratumorally injected in several clinical trials to enhance the anti-tumor immune response elicited by immune checkpoint antibodies. However, they have shown minimal effect, suggesting the importance of optimizing the dose and route of administration for STING agonists and deciphering other immune pathways that contribute to anti-tumor immune responses. Recent studies have revealed that AIM2 activity induces pro-tumor growth through multiple parallel pathways, including inhibition of STING-type I IFN signaling. Thus, AIM2 could be a potential molecular target for cancer immunotherapies. This review summarizes the current research on the roles of cGAS, STING, and AIM2 in immune cells and tumor cells in the tumor microenvironment and discusses the future prospects of anti-tumor treatment approaches based on these molecules.
cGAS和AIM2是在胞质双链DNA存在时被激活的胞质DNA传感器，在包括免疫细胞和肿瘤细胞在内的多种细胞类型中表达。肿瘤浸润树突状细胞（TIDC）胞质溶胶中的胞质DNA传感器识别肿瘤来源的双链DNA可激活先天性和获得性免疫，从而增强抗肿瘤免疫反应。STING是cGAS的下游信号效应器，可诱导I型干扰素（IFN）信号传导。由于其激活TIDC的能力，STING激动剂已在多项临床试验中进行瘤内注射，以增强免疫检查点抗体引发的抗肿瘤免疫反应。然而，它们的效果甚微，这表明优化STING激动剂的剂量和给药途径以及解读其他有助于抗肿瘤免疫反应的免疫途径非常重要。最近的研究表明，AIM2活性通过多种平行途径诱导肿瘤生长，包括抑制STING-I型干扰素信号传导。因此，AIM2可能是癌症免疫治疗的潜在分子靶点。本综述总结了目前关于cGAS、STING和AIM2在肿瘤微环境中的免疫细胞和肿瘤细胞中的作用的研究，并讨论了基于这些分子的抗肿瘤治疗方法的未来前景。
