The activation of cGAS-STING pathway offers novel therapeutic opportunities in cancers

• Published in: Frontiers in immunology Vol. 16; p. 1579832
• Main Authors: Wang, Yumin, Zhu, Yonglin, Cao, Yuwei, Li, Yulin, Zhang, Zhe, Fleishman, Joshua S., Cheng, Sihang, Chen, Jichao, Ding, Mingchao
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 09.06.2025
• Subjects: agonist; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; cancers contents; CGAS; Humans; Immunology; Membrane Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Nucleotidyltransferases - metabolism; Signal Transduction - drug effects; small-molecule compounds; STING; CGAS; STING; agonist; cancers contents; small-molecule compounds
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2025.1579832

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway are crucial elements of the type I interferon (type I IFN) response. cGAS senses both exogenous and endogenous DNA within cells, labeling cGAS-STING as a pivotal anti-tumor immunity mechanism, autoimmunity, sterile inflammatory responses, and cellular senescence. The cGAS-STING pathway, a pivotal innate immune axis, modulates tumorigenesis via diverse effector responses. Emerging evidence have shown that activating of cGAS-STING pathway functions as a therapy to kill cancers. Insights into the biology of the cGAS-STING pathway have enabled the discovery of small-molecule agents which have the potential to activate cGAS-STING axis in cancers. In this review, we first outline the principal components of the cGAS-STING signaling cascade. Then we explore recent advancements in understanding the cGAS-STING signaling pathway, with particular emphasis on its activation mechanisms and roles in tumor cancer killing. Next, we summarize a list of bioactive small-molecule compounds which activate the cGAS-STING axis, reviewing their potential applications. Finally, we discuss key limitations of this new proposed therapeutic approach and provide possible techniques to overcome them. This review highlights a novel groundbreaking therapeutic possibilities through activating cGAS-STING in cancers.