Targeting cGAS-STING: modulating the immune landscape of hepatic diseases

Abstract

Liver diseases, including viral hepatitis, alcoholic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC), represent a significant threat to global health due to their high mortality rates. The cGAS-STING pathway, a critical part of the innate immune system, plays a crucial role in detecting cytoplasmic DNA and initiating immune responses, including autoimmune inflammation and antitumor immunity. Genomic instability during cancer progression can trigger this pathway by releasing DNA into the cytoplasm. Emerging research indicates that cGAS-STING signaling is intricately involved in maintaining liver homeostasis and contributes to the pathogenesis of various liver diseases. This review outlines the cGAS-STING pathway, with a particular focus on its activation mechanism and its roles in several notable liver conditions. Specifically, we explore the complex interplay of cGAS-STING signaling in viral hepatitis, ALD, MASLD, and HCC, and discuss its potential as a therapeutic target. For example, in HCC, strategies targeting cGAS-STING include using nanomaterials to deliver STING agonists, combining radiofrequency ablation (RFA) with cGAS-STING activation, and leveraging radiotherapy to enhance pathway activation. Furthermore, modulating cGAS-STING activity may offer therapeutic avenues for viral hepatitis and chronic liver diseases like MASLD and ALD, either by boosting antiviral responses or mitigating inflammation. This review highlights the complex role of cGAS-STING signaling in these specific liver diseases and underscores the need for further research to fully realize its therapeutic potential.

Keywords: alcoholic liver disease; cGAS-STING; hepatocellular carcinoma; metabolic dysfunction-associated steatotic liver disease; tumor immune microenvironment; viral hepatitis.

Figure 1

The cGAS-STING signaling pathway and its role in innate immunity. This illustration depicts the activation and downstream signaling cascade of the cGAS-STING pathway, a crucial component of the innate immune response to cytosolic DNA. Various sources, including dead cells, tumor cells, DNA and retroviruses, and self-DNA, can release dsDNA into the cytoplasm, triggering cGAS activation. Upon binding to dsDNA, cGAS catalyzes the synthesis of cGAMP, which acts as a second messenger to activate STING on the ER. Activated STING translocates to the Golgi apparatus, where it activates TBK1, leading to the phosphorylation of both STING and IRF3. Phosphorylated IRF3 dimerizes and induces the transcription of IFN-I. Simultaneously, STING activates IKK, resulting in the release and nuclear translocation of NF-κB, which promotes the transcription of pro-inflammatory cytokines. IFN-I, in turn, binds to its receptor (IFNAR) and initiates the JAK-STAT signaling pathway, leading to the expression of ISGs. These ISGs contribute to diverse immune responses, including enhanced antigen presentation, T cell and NK cell activation, antibody production, and direct pathogen elimination. The cGAS-STING pathway also regulates the inflammatory response through autophagy, which can degrade STING.

Figure 2

The cancer-immunity cycle in the hepatocellular carcinoma (HCC) tumor microenvironment. This illustration depicts the seven key steps involved in the cancer-immunity cycle, highlighting the dynamic interplay between tumor cells and the immune system within the HCC TME. The cycle is initiated by the release of tumor-specific antigens (neoantigens) from dying tumor cells (step 1). Dendritic cells (DCs) capture these antigens and migrate to lymph nodes, where they present them to T cells (steps 2 and 3). This presentation activates and primes antigen-specific CD8+ T cells (step 4), which then traffic to and infiltrate the TME (step 5). Within the TME, these activated T cells recognize and bind to tumor cells displaying the corresponding antigens (step 6), leading to tumor cell destruction (step 7). This cycle represents a critical process in anti-tumor immunity, but can be disrupted by various mechanisms employed by tumor cells to evade immune surveillance. Understanding the intricacies of the cancer-immunity cycle in HCC is crucial for developing effective immunotherapeutic strategies.

Figure 3

Activation of the cGAS-STING pathway transforms the tumor microenvironment from a “cold” to a “hot” state. The “cold” tumor microenvironment is characterized by a low density of immune cells, including Tregs, MDSCs, M2 macrophages, and NK cells, resulting in limited anti-tumor immunity. Activation of the STING pathway, triggered by IFN-I, induces a shift to a “hot” tumor microenvironment. This “hot” state features an influx of cytotoxic immune cells, such as CD8+ T cells, DCs, and M1 macrophages, indicating a robust anti-tumor immune response. This transition is facilitated by IFN-I-mediated enhancement of tumor cell immunogenicity, recruitment of effector immune cells, and suppression of immunosuppressive cell activity.

Figure 4

Activation of the cGAS-STING pathway in hepatocellular carcinoma (HCC) by various stimuli, including radiotherapy. Radiofrequency ablation, cell death, radiation, and nanomedicine can induce the release of mitochondrial DNA and/or dsDNA. This dsDNA binds to cGAS, leading to the production of cGAMP. cGAMP acts as a second messenger, activating STING localized in the ER. Activated STING translocates to the Golgi apparatus, where it recruits and activates TBK1 and IKK. TBK1 phosphorylates IRF3, leading to its dimerization and translocation to the nucleus, where it induces the expression of IFN. IKK phosphorylates IκB, leading to its degradation and the release of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB also translocates to the nucleus and induces the expression of pro-inflammatory cytokines. IFN released from the tumor cells can act in an autocrine or paracrine manner to upregulate MHC-I expression, promoting antigen presentation to CD8+ T cells. This can lead to cross-priming and activation of anti-tumor immunity. IFN can also promote DC maturation, resulting in enhanced antigen presentation and T cell activation. Additionally, IFN can reduce the number of regulatory T cells (Treg cells) and MDSC cells, which suppress anti-tumor immunity. These processes collectively contribute to the anti-tumor immune response and enhance the efficacy of radiotherapy in HCC.

Figure 5

Mechanisms of HBV evasion and activation of the cGAS-STING pathway. HBV employs multiple strategies to evade detection by the cGAS-STING pathway, including nucleocapsid shielding of viral DNA, HBx-mediated cGAS degradation, epigenetic silencing and nuclear relocalization of cGAS, and disruption of STING ubiquitination by HBV polymerase. Despite these evasion tactics, activation of the cGAS-STING pathway through STING agonists can enhance antiviral activity by increasing the production of interferons (IFNs) and interferon-stimulated genes (ISGs). cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes; cccDNA, covalently closed circular DNA; rcDNA, relaxed circular DNA; pgRNA, pregenomic RNA; sgRNA, subgenomic RNA; HBx, HBV X protein; HAT1, histone acetyltransferase 1; miR-181a-5p, microRNA-181a-5p; KPNA2, karyopherin subunit alpha 2; cGAS mRNA, cyclic GMP-AMP synthase messenger RNA.

Figure 6

Mechanisms of cGAS-STING pathway activation in MASLD/MASH. A high-fat diet contributes to mitochondrial damage and ER oxidative stress, leading to the release of mtDNA and other damage-associated molecular patterns (DAMPs). Cytosolic mtDNA activates the cGAS-STING pathway, resulting in the production of cGAMP. cGAMP acts as a second messenger, binding to and activating STING located on the ER membrane. Activated STING translocates to the Golgi apparatus where it recruits and activates TBK1. TBK1 subsequently phosphorylates IRF3, promoting its dimerization and nuclear translocation. Nuclear IRF3, along with NF-κB, induces the transcription of pro-inflammatory cytokines, contributing to the inflammatory response characteristic of MASLD/MASH. Additionally, dead cells can release dsDNA, which further activates the cGAS-STING pathway, amplifying the inflammatory response.

Figure 7

The role of cGAS-STING signaling in alcoholic liver disease (ALD). Excessive alcohol consumption (EtOH) disrupts gut barrier integrity, leading to increased translocation of gut-derived bacteria and bacterial DNA. This, coupled with ethanol-induced mitochondrial damage and release of mtDNA, activates the cGAS-STING pathway. cGAS binds to bacterial or mtDNA, producing cGAMP. cGAMP then activates STING, located on the ER, triggering downstream signaling that culminates in IRF3 phosphorylation and activation. Activated IRF3 translocates to the nucleus, promoting the expression of pro-inflammatory cytokines. Notably, cGAMP can also be transferred to neighboring hepatocytes via connexin 32 (Cx32) gap junctions, amplifying the inflammatory response. This intercellular signaling contributes to hepatocyte death and the progression of ALD. Targeting cGAS, STING, or Cx32 could offer therapeutic strategies to mitigate liver injury in ALD by dampening the inflammatory cascade.