The cGAS-STING pathway: a dual regulator of immune response in cancer and therapeutic implications

Abstract

While the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway promotes anti-tumor immunity by detecting cytoplasmic DNA and inducing type I interferons, it also facilitates immune evasion through PD-L1 upregulation. Autophagy enhances cGAS signaling by delivering it to autophagosomes, boosting DNA sensing, while phase separation into liquid droplets further amplifies its activity and regulates autophagy, affecting tumor proliferation. Oxidative stress and DNA damage activate cGAS-STING, triggering pro-inflammatory cytokines that drive chronic inflammation and metabolic disorders. Interactions with immune checkpoint inhibitors augment T cell responses against tumors, yet concurrent PD-L1 induction underscores a complex balance between activation and suppression. Therapeutic strategies-combining DNA damage response inhibitors with checkpoint blockade-show promise in amplifying antitumor immunity. Moreover, post-translational modifications, including m6A methylation and acetylation, fine-tune cGAS function and downstream signaling. Together, these insights reveal the dualistic nature of cGAS-STING in cancer, offering avenues for targeted interventions that leverage its immunostimulatory potential while mitigating mechanisms of immune escape. Additionally, cGAS-driven inflammation links to metabolic dysfunction and chronic disease, underscoring its broad clinical relevance.

Keywords: Autophagy; Immune response; Therapeutic strategies; Tumor evasion; cGAS-STING pathway.

Fig. 1

The Relationship Between Oxidative Stress and DNA Damage: DNA damage is often accompanied by increased oxidative stress. The accumulation of ROS can directly lead to DNA damage and trigger a series of cellular responses, including inflammation and apoptosis. This oxidative stress is a significant contributor to cellular aging. Promotion of Cellular Aging by Oxidative Stress: Under conditions of oxidative stress, chromatin fragments can be released into the cytoplasm. These released chromatin fragments are seen as a cellular response to damage and may further trigger inflammatory responses and cellular aging. Activation Mechanism of cGAS: Oxidative stress promotes the entry of free DNA into the cytoplasm, which in turn activates cGAS. cGAS can recognize double-stranded DNA in the cytoplasm, leading to the synthesis of cGAMP, which activates the downstream STING signaling pathway. This pathway plays a crucial role in regulating the immune response of cells to oxidative damage. Relationship Between ROS and Mitochondrial DNA. Increased levels of ROS can lead to changes in the intracellular environment, promoting mitochondrial damage and the release of mtDNA. cGAS can recognize mtDNA in the cytoplasm, and radiation-induced cellular damage is often closely associated with the generation of ROS. Interactions of the cGAS-STING Pathway with Cell Death Mechanisms: The activated cGAS-STING pathway interacts with mechanisms of cell death, including the activation of the NLRP3 inflammasome. This interaction leads to the release of pro-inflammatory cytokines (such as IL-1β and IL-18), which further exacerbate tissue damage

Fig. 2

Activation of STING and Its Key Role in Antiviral and Antitumor Immunity: STING plays a crucial role in recruiting TBK1, which is essential for activating the innate immune response against viral infections and tumors. STING enhances the immune response by promoting the expression of inflammation-related factors through its interaction with cGAMP. Regulation of the STING Signaling Pathway by NF-κB: NF-κB, as a key transcription factor, enhances the STING signaling pathway by regulating the intracellular transport of STING. The activation of NF-κB alters the cellular localization of STING, facilitating its transport to the cell membrane and increasing its chances of binding with cytoplasmic DNA, thereby amplifying the strength of the STING signal. Dual Activation of the STING-TBK1-IRF3 Signaling Pathway: Once TBK1 is recruited by STING, TBK1 undergoes a conformational change that enhances its kinase activity and activates the IRF3 and NF-κB pathways. This dual activation promotes the production of type I interferons and pro-inflammatory cytokines, enhancing the immune system’s ability to recognize and eliminate tumor cells. Role of STING in Major Immune Cells: In myeloid cells, STING activates the NF-κB signaling pathway, promoting the production of inflammatory factors. TBK1 and IKKε (IκB kinase ε) play redundant roles in STING-mediated NF-κB activation. They can compensate for each other to ensure the effective activation of the STING signaling pathway. Crosstalk and Regulation of Cell Fate by the cGAS-STING Pathway: cGAS not only promotes adaptive immune responses but also participates in local immune responses by activating innate immune cells such as dendritic cells and macrophages. The crosstalk of cGAS with other signaling pathways enhances the immune response and promotes the release of cytokines, thereby boosting T cell responses. Additionally, the activation of the cGAS-STING pathway influences the process of cellular senescence and immunological tolerance by regulating autophagy and translational selectivity. ER: Endoplasmic Reticulum

Fig. 3

cGAS: Bridging Immune Surveillance and Tumor Biology cGAS enhances the recognition of cytosolic DNA by promoting autophagy and interacting with STING, thereby facilitating immune responses while regulating intracellular metabolism and homeostasis. As a key sensor, cGAS recognizes DNA damage within the cell and activates the cGAS-STING pathway, promoting antitumor immune responses while influencing the immune evasion mechanisms of tumor cells. Under oxidative stress conditions, cGAS identifies cytosolic DNA and activates the cGAS-STING signaling pathway, thereby enhancing antiviral and inflammatory responses, while also participating in apoptosis and the activation of inflammasomes, further influencing cellular senescence. cGAS serves as an intracellular DNA sensor that, through the activation of the cGAS-STING signaling pathway, promotes cellular senescence and chronic inflammation, impacting cell death mechanisms and contributing to the development of autoimmune and metabolic diseases. In the tumor microenvironment, cGAS activates the STING signaling pathway by recognizing DNA released from tumor cells, enhancing immune responses, promoting T-cell infiltration, and facilitating the formation of immune memory. However, its activation may also increase PD-L1 expression, promoting tumor immune evasion and progression. cGAS plays a pivotal role in antitumor immunity by activating the STING pathway to mobilize inflammatory and immune responses, while also enhancing cellular response to endogenous and exogenous threats through interactions with signaling pathways such as NF-κB and PERK. The activity of cGAS is influenced by various regulatory mechanisms, including acetylation and m6A modification, which enhance cGAS's ability to bind DNA and regulate its expression, thereby promoting antiviral and antitumor immune responses. cGAS plays a critical role in ferroptosis and cuproptosis by activating the cGAS-STING pathway, promoting the death of tumor cells and the polarization of macrophages, thereby enhancing antitumor immune responses and modifying the tumor microenvironment, which affects tumor progression. As a key immune surveillance factor, cGAS recognizes bacterial DNA in the gut microbiome and regulates inflammatory responses, while also enhancing antiviral immune responses through the cGAS-STING-IFN-I axis, with its activity influenced by the composition of the gut microbiome and its metabolites. In the tumor microenvironment, cGAS regulates immune responses through the cGAS-STING pathway, for example, by promoting the secretion of IL-6, impacting the immune evasion of tumor cells, while also enhancing the response to immunotherapy by regulating DNA damage responses and augmenting the functions of cytotoxic T cells. PERK: Protein Kinase R-Like Endoplasmic Reticulum Kinase