Nature系列综述：傅阳心/卢长征系统解读靶向cGAS-STING通路在癌症治疗中的机遇与挑战

Core Viewpoint - The cGAS-STING pathway plays a crucial role in detecting tumor-derived DNA, influencing both spontaneous and treatment-induced responses, and establishing a delicate balance between pathological inflammation and protective immune responses [2][3]. Group 1: Overview of cGAS-STING Pathway - The review published in Nature Reviews Cancer discusses the dual roles of the cGAS-STING pathway in cancer, highlighting both its pro-cancer and anti-cancer effects [5]. - It provides a comprehensive analysis of the diverse sources of cGAS-STING activating ligands and their prevalence in various human cancers, including DNA abnormalities caused by chromosomal instability, replication stress, telomere shortening, and treatment-induced DNA damage [7][8]. Group 2: Dual Role in Tumor Progression - The review emphasizes the different outcomes mediated by cGAS-STING activation at various stages of tumor initiation, progression, and metastasis, noting its critical anti-tumor role during tumor initiation and potential pro-tumor effects during tumor progression [8][12]. Group 3: Clinical Implications and Challenges - The review systematically reviews clinical trial results of STING agonists, such as ADU-S100 and MK-1454, and analyzes the limited efficacy due to factors like short drug half-life and differences in tumor microenvironments between humans and mice [14]. - It details the multi-layered negative regulatory networks that limit the anti-tumor effects of the cGAS-STING pathway, including DNA uptake barriers and differential responses of innate and adaptive immune cells [14]. Group 4: Future Directions - The review proposes several optimization strategies for enhancing the efficacy of cGAS-STING-targeted therapies, such as selective induction of mitochondrial DNA release and the development of drug delivery systems that enable spatiotemporal control of activation [15]. - It also suggests that transient inhibition of cGAS-STING signaling may normalize immune responses and enhance the effectiveness of immunotherapy, referencing recent successful cases in early clinical trials [16][17].