Organelle-specific signaling of cGAS-STING

Shengduo Liu; Ailian Wang; Chen Chen; Pinglong Xu

doi:10.1016/j.tcb.2025.08.007

Organelle-specific signaling of cGAS-STING

Trends Cell Biol. 2025 Sep 19:S0962-8924(25)00198-9. doi: 10.1016/j.tcb.2025.08.007. Online ahead of print.

Authors

Shengduo Liu¹, Ailian Wang², Chen Chen², Pinglong Xu³

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Intelligent Medicine, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 311215, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
² Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
³ Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Intelligent Medicine, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 311215, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Cancer Center, Zhejiang University, Hangzhou 310058, China. Electronic address: xupl@zju.edu.cn.

PMID: 40975693
DOI: 10.1016/j.tcb.2025.08.007

Abstract

Innate immune sensing through cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) surveils cytosolic DNA from invading pathogens or damaged organelles and initiates a spectrum of immune responses. It is well established that upon 2'3'-cyclic GMP-AMP (cGAMP) binding, STING exits the endoplasmic reticulum (ER), traverses the Golgi to trigger interferon programs, and finally reaches lysosomes for signal resolution through degradation, revealing a tightly choreographed itinerary for cytokine-driven immunity. However, emerging studies reveal additional layers of spatiotemporal complexity: ER-resident STING tunes in messenger RNA translation and Ca²⁺ efflux, Golgi-localized STING functions as a proton channel that initiates H⁺-dependent autophagy and transcription factor EB-directed programs for organelle homeostasis, and various mechanisms for metabolic remodeling and cell fate determination. This review synthesizes emerging organelle-specific mechanisms of cGAS-STING, delineates their roles in physiology and disease, and discusses how an organelle-centric perspective may inform selective, context-sensitive immunotherapies.

Keywords: cGAS–STING; cellular function; innate immunity; organelle; signaling mechanism; trafficking.

Publication types

Review