Advances in the prerequisite and consequence of STING downstream signalosomes

Abstract

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining conserved. Aside from recognizing pathogens through conserved motifs, these receptors also detect aberrant or misplaced self-molecules as possible signs of perturbed homeostasis. Upon binding external or self-derived DNA, a mobile secondary messenger 2'3'-cyclic GMP-AMP (cGAMP) is produced by cGAS and in turn activates its adapter STING in the endoplasmic reticulum (ER). Resting-state or activated STING protein is finely restricted by multiple degradation machineries. The post-translational changes of the STING protein, along with the regulatory machinery of the secret routes, limit the onset, strength and sustention of STING signal. STING experiences a conformational shift and relocates with TBK1 from the ER to perinuclear vesicles containing transcription factors, provoking the transcription activity of IRF3/IFN-I and NF-κB pathways, as well as to initiate a number of cellular processes that have been shown to alter the immune landscape in cancer, such as autophagy, NLRP3 inflammasome, ER stress, and cell death. STING signal thus serves as a potent activator for immune mobilization yet also triggers immune-mediated pathology in tissues. Recent advances have established the vital role of STING in immune surveillance as well as tumorigenic process. This review provides an overview of the disparate outcomes of cancer attributed to the actions of pleiotropic and coordinated STING downstream signalosomes, along with the underlying mechanisms of STING function in pathologies, providing therapeutic implications for new approaches in hunt for the next generation of cancer immunotherapy base on STING.

Keywords: cancer therapeutics; cellular heterogeneity; signalosomes; stimulator of interferon genes.

Figure 1:

Overview of the cGAS/STING signal transduction pathway. Cytosolic DNA accumulates in response to pathogen infections (e.g., viruses and bacteria) and homeostasis perturbations (e.g., surrounding dead cells). DNA sensors, such cGAS, senses misplaced dsDNA of chromatin, mitochondria, PAMP or DAMP. cGAMP is synthesized by cGAS and then activates its adapter STING, which undergoes a conformational shift and relocates with TBK1 from the ER to perinuclear vesicles containing transcription factors, provoking the transcription activity of IRF3/IFN-I and NF-κB pathways, as well as to initiate a number of cellular processes such as autophagy and NLRP3 inflammasome activation. The degradation of STING occurs in the lysosome, which is accessible by Golgi trafficking or autophagosomes by STING. Figure was illustrated by Figdraw (www.figdraw.com). cGAS, cyclic GMP-AMP synthase; cGAMP, 2′3′-cyclic GMP-AMP; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; IKK, IκB kinase; IFN-I, type I interferon; ERGIC, endoplasmic reticulum–Golgi intermediate compartment.

Figure 2:

Diverse outcomes arise from cell preference of STING activation. Tumor infiltrated cells secret a second messenger cGAMP into the surrounding as the tumors grow. STING is universally expressed in a variety of cell subsets. Thereby the surrounding cells exhibit preference to STING downstream effects. STING activation in dendritic cells (DC) and cancer cells promotes IFN-I production and anti-tumor responses. STING activation in adaptive immune cells result in T cell death and regulatory B cell induction. Intrinsic STING signal in cancer cells also promote its survival and metastasis. Thus, cytocial delivery system, such as LNPs, ADC, and exosomes, allows precise spatiotemporal and control over the STING signaling. Figure was illustrated by Figdraw. cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes; DC, dendritic cells; IFN-I, type I interferon; LNPs, lipid nanoparticles; ADC, antibody-drug conjugates.

Figure 3:

The number of articles retrieved in Google Scholar with key words of “stimulator of interferon genes” and “cancer immunotherapy”.