This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g. "cgas_sting_pathway_activation#TBK1-IRF3 Activation and Type I Interferon Induction"). Key disorder-specific substitutions at the entry nodes are: cytosolic nuclease loss (TREX1, RNASEH2A/B/C, SAMHD1) in Aicardi-Goutieres syndrome; ligand-independent STING1 gain-of-function variants in SAVI; failed Golgi-to-ER retrieval of STING in COPA syndrome; tumor-derived and micronuclear DNA taken up by antigen-presenting cells in cancer immunosurveillance; and pharmacologic agonists, which bypass cGAS entirely and enter at the STING node.
Scope boundaries. This module is the DNA-sensing arm specifically, and is deliberately narrower than `innate_antiviral_interferon_response`, which covers pattern-recognition receptor sensing and the JAK-STAT interferon response generally; a viral entry may conform to both, at different nodes. What is proprietary to this module is the trafficking step, which is where two of the three interferonopathies place their lesion, and the signal-strength bifurcation, which is why the same node is a drug target in two opposite directions. It is not an Xogenesis module: nothing pathological is formed, a signalling pathway runs when and where it should not.
A conforming node must evidence STING-dependence, not merely an interferon signature. A raised interferon score is the shared readout of every type I interferonopathy, including the RNA-sensing (MDA5/IFIH1) and proteasome-associated ones that do not run through this pathway at all, so the signature alone does not establish conformance. Conversely, the NF-kB arm that TBK1 recruitment also switches on is interferon-independent (PMID:33785602) and is not modelled as a separate node here; an entry whose evidence is specifically for that arm should say so in prose rather than conforming to the interferon node.
How much of the preclinical STING agonist adjuvant literature transfers to humans, given that the most widely used tool agonist activates mouse STING but not human STING?
HUMAN MODEL MISMATCH
OPEN
human_model_mismatch_sting_agonist_species_specificity
Attached to:
STING Oligomerization and ER-to-Golgi Translocation
Th1-Polarized T Cell Priming and Antitumor Immunity
DMXAA, the flavonoid agonist behind a large fraction of the preclinical STING adjuvant and in situ vaccine literature, engages mouse STING and not the human receptor, and its failure in phase III lung cancer trials preceded rather than followed that discovery. Work in this area therefore depends on constructions that do not exist in patients: humanized STING mice, mouse STING delivered as an mRNA transgene into a human-STING background, or engineered human STING variants such as S162A/G230I/Q266I selected precisely for the DMXAA responsiveness wild-type human STING lacks. Each is a legitimate experimental device and each puts a species barrier between the result and a human claim. The mismatch is not about effect size, because it is not the potency of the response that differs but whether the compound engages the receptor at all. Curators should record the agonist chemotype and the receptor species when citing this arm, and should not carry a DMXAA-based efficacy result into a human disease entry as though it were a general property of STING agonism. The non-nucleotide human agonists (MSA-2) and the cyclic dinucleotides do not have this problem, which is why they, not DMXAA, are the appropriate citation for a human-directed claim.
Proposed experiments:
Cell-restricted STING activation in primary human antigen-presenting cells
Agonist response in human tumor and adjacent normal tissue explants
What magnitude and duration of STING signalling separates the immunostimulatory arm from the lymphocyte-apoptotic, regulatory B cell and translation-suppressing arms, and is there a measurable biomarker of that threshold?
KNOWLEDGE GAP
OPEN
knowledge_gap_sting_signal_strength_threshold
Attached to:
TBK1-IRF3 Activation and Type I Interferon Induction
Signal-Strength-Dependent Lymphocyte Apoptosis and Regulatory B Cell Induction
Suppression of Cap-Dependent mRNA Translation
The whole branch structure of this module rests on the claim that intensity and chronicity determine whether the pathway protects or harms, but that claim is currently qualitative. No validated threshold exists in any units a curator or a trial could use, and the available readouts do not resolve it: a peripheral blood interferon signature is a composite score that saturates, phospho-TBK1 by flow cytometry is a snapshot of a transient event that is then reversed by autophagic degradation of STING itself, and neither is measured per cell type in the tissue where the decision is being made. This matters in both directions. On the therapeutic side it is why agonist dose optimization has been empirical and why monotherapy trials failed without a prospective way to tell an immunostimulatory exposure from an immunosuppressive one. On the disease side it is why it remains unclear whether the milder STING1 gain-of-function alleles sit below a threshold or on a continuum with the severe ones. Until this is resolved, the productive and counter-regulatory arms of this module should be curated as separate claims with their own evidence, and a disorder entry should not infer one from the other.
Proposed experiments:
Dose-by-duration response surface for the divergent STING outcomes
Per-cell-type signalling readout as a candidate threshold biomarker
Cytosolic DNA Accumulation and cGAS-Dependent cGAMP Synthesis
trigger
Double-stranded DNA reaching the cytosol, from any source, is bound by cyclic GMP-AMP synthase (cGAS), which on binding assembles into higher-order cGAS-DNA complexes and synthesizes the second messenger 2'3'-cGAMP. Because cGAS recognizes DNA as such rather than any pathogen-specific feature, the ligand may be microbial, tumor-derived, mitochondrial, micronuclear, or retroelement-derived self DNA; the safeguard against spurious self activation is nucleic acid compartmentalization plus continuous cytosolic nuclease clearance, not ligand discrimination. Disorder-specific substitutions at this node: loss of TREX1, RNASEH2A/B/C or SAMHD1 in Aicardi-Goutieres syndrome; mitochondrial DNA release under cellular stress; micronuclei generated by chromosomal instability in cancer; tumor DNA taken up by tumor-resident dendritic cells. Pharmacologic STING agonists do not act here at all, and instead bypass this node.
Downstream
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STING Oligomerization and ER-to-Golgi Translocation
cGAMP binds the STING ligand-binding domain at the endoplasmic reticulum membrane, driving the conformational change and oligomerization that license export.
Show evidence (2 references)
"Underlying this broad involvement of the cGAS-STING pathway is its capacity to sense and regulate the cellular response towards microbial and host-derived DNAs, which serve as ubiquitous danger-associated molecules."
Establishes that the sensing step is agnostic to the origin of the DNA, which is what allows one module trigger to cover pathogen, tumor and self DNA routes. Evidence source is OTHER because this is a review.
"In this study, we show that Trex1 (-/-) mice lacking cGAS are completely protected from lethality, exhibit dramatically reduced tissue inflammation, and fail to develop autoantibodies."
Genetic epistasis placing cGAS upstream of the disease in the Trex1-null model of Aicardi-Goutieres syndrome, establishing that undegraded self DNA drives the pathway through this node rather than through a parallel sensor. Evidence source is MODEL_ORGANISM (Trex1-null mice).
STING Oligomerization and ER-to-Golgi Translocation
amplifier
Ligand-bound STING dimers undergo conformational rearrangement, oligomerize side by side, and are exported from the endoplasmic reticulum in COPII vesicles through the ER-Golgi intermediate compartment to the Golgi, where downstream kinase recruitment occurs. Trafficking is the regulated, rate-setting step of the axis rather than a passive relocation: at steady state STING is continuously retrieved from the Golgi to the ER by COPI vesicles, so signalling reflects the balance between anterograde export and retrograde retrieval. This is the node at which two of the three monogenic interferonopathies place their lesion, and the node at which every pharmacologic agonist acts. Substitutions: ligand-independent STING1 gain-of-function variants (SAVI); failed COPI-dependent retrieval with accumulation of ER-resident STING at the Golgi (COPA syndrome); cyclic dinucleotide agonists such as 2'3'-cGAMP and non-nucleotide agonists such as MSA-2 (human) or DMXAA (mouse) occupying the ligand-binding domain.
Downstream
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TBK1-IRF3 Activation and Type I Interferon Induction
Oligomerized STING at the ERGIC and Golgi recruits TBK1 through its C-terminal tail, the obligatory step for downstream transcription factor activation.
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Suppression of Cap-Dependent mRNA Translation
The non-canonical arm: ER-resident STING activates PERK directly, which phosphorylates eIF2-alpha and blocks translation initiation ahead of and independently of TBK1-IRF3. Drawn from this node rather than from TBK1-IRF3 so the interferon-independent route is not modelled as a consequence of the step it bypasses; the interferon-dependent IFNAR1/IRF9/4E-BP1 route retains its edge from TBK1-IRF3 Activation.
Show evidence (3 references)
"trafficking of STING is facilitated by the canonical ER-to-Golgi transport machinery composed of coatomer protein complex II (COPII) vesicles, relying on the GTPase SAR1A and the COPII complex components, including SEC24C as well as the ARF-GTPase ARF1"
Names the export machinery that makes trafficking a discrete, druggable and genetically breakable step rather than an assumed consequence of ligand binding. Evidence source is OTHER because this is a review.
"We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi."
Shows a human disease gene acting on this node specifically, by failing to return STING from the Golgi rather than by increasing ligand. Evidence source is IN_VITRO (overexpression and silencing in cell lines).
"Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation."
Establishes the ligand-independent entry route: in SAVI the receptor is already maximally on, so the pathway cannot be driven higher by adding ligand. Evidence source is HUMAN_CLINICAL (patient cells).
TBK1-IRF3 Activation and Type I Interferon Induction
central effector
STING recruits TANK-binding kinase 1 to its C-terminal tail; TBK1 autophosphorylates, phosphorylates STING at Ser366 (Ser365 in mouse), and phosphorylates the recruited interferon regulatory factor 3, which dimerizes and translocates to the nucleus to drive transcription of type I interferons and other inflammatory mediators. This is the disorder-agnostic, rate-limiting node of the module and the key conformance target: every route into the pathway, genetic or pharmacologic, converges here, and downstream biology is a function of how strong and how sustained this signal is rather than of how it was initiated. TBK1 recruitment also activates NF-kB independently of interferon induction, so loss of the IRF3 arm alone does not abolish STING-dependent antiviral and antitumor immunity.
Downstream
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Interferon-Stimulated Gene Expression and Antigen-Presenting Cell Maturation
Secreted type I interferon acts on the interferon receptor to induce interferon-stimulated genes and mature antigen-presenting cells.
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Chronic Type I Interferon-Driven Tissue Inflammation
When the signal is constitutive rather than transient, sustained interferon output becomes the driver of tissue injury.
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Signal-Strength-Dependent Lymphocyte Apoptosis and Regulatory B Cell Induction
Intense STING signalling in lymphocytes, which express the receptor as readily as myeloid cells do, engages a distinct proapoptotic and regulatory transcriptional program.
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Suppression of Cap-Dependent mRNA Translation
Interferon-stimulated gene products and a parallel STING-PERK arm converge on translation initiation factors to restrain cap-dependent protein synthesis.
Show evidence (2 references)
"These results demonstrate that STING can function independently of type I interferons and autophagy, and that TBK1 recruitment to STING is essential for antiviral and antitumor immunity."
Separates the TBK1 recruitment step, which is indispensable, from the IRF3 and interferon arm, which is not, using point-mutant mouse strains that break one without the other. This is why the node is named for TBK1 recruitment and not for interferon alone. Evidence source is MODEL_ORGANISM (S365A, L373A and delta-CTT knock-in mice).
"The parameters that dictate host-protective versus pathogenic activity are still being unfolded, but it appears that the intensity and chronicity of cGAS-STING signalling are major determinants in most cases."
States the signal-strength principle on which this module's branch structure rests: the same node yields protective immunity or disease depending on magnitude and duration. Evidence source is OTHER because this is a review.
Interferon-Stimulated Gene Expression and Antigen-Presenting Cell Maturation
effector
Autocrine and paracrine type I interferon induces interferon-stimulated genes and matures dendritic cells and macrophages: costimulatory CD86 and MHC class II are upregulated, cross-presentation of acquired antigen improves, and CXCL9, CXCL10 and CCL5 are secreted, recruiting effector T cells and further dendritic cells into the tissue. This is the arm the adjuvant and immunotherapy literature is built on, and it is myeloid-cell centred: the therapeutic effect tracks with activation in antigen-presenting cells rather than with total pathway activation across all cell types.
Downstream
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Th1-Polarized T Cell Priming and Antitumor Immunity
Matured antigen-presenting cells cross-prime antigen-specific CD8+ T cells and polarize CD4+ helper responses toward Th1.
Show evidence (2 references)
"Spontaneous tumor-initiated T cell priming is dependent on IFN-β production by tumor-resident dendritic cells."
Places dendritic-cell interferon production between pathway activation and T cell priming, which is the causal content of this node. Evidence source is MODEL_ORGANISM (syngeneic mouse tumor models).
"Intratumoral or subcutaneous LNPs are preferentially internalized by myeloid cells, preserving antigen expression fidelity, achieving localized STING activation in antigen-presenting cells and preventing systemic regulatory B cell differentiation and immunocyte apoptosis."
Demonstrates that restricting activation to antigen-presenting cells is what separates the productive arm of this node from the counter-regulatory arms below. Evidence source is MODEL_ORGANISM (humanized STING mouse models).
Th1-Polarized T Cell Priming and Antitumor Immunity
consequence
Cross-primed antigen-specific CD8+ cytotoxic T cells and Th1-polarized CD4+ helper cells expand, infiltrate tumor tissue, and mediate regression, with immunologic memory sufficient to reject rechallenge and, after local administration, untreated distant lesions. This is the outcome that motivates STING agonists as vaccine adjuvants and as intratumoral in situ vaccines, and it is the arm a cancer entry conforms to. It is the therapeutic mirror image of the chronic inflammation arm, not a different pathway.
Show evidence (2 references)
"IT injection of STING agonists induced profound regression of established tumors in mice and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory."
Documents the systemic, memory-bearing antitumor response produced by driving this axis locally. Evidence source is MODEL_ORGANISM (mouse tumor models).
"The Syn-STING vaccine elicits robust adaptive responses and Th1-biased T cell immunity."
Confirms the Th1 rather than Th2 polarization of the adaptive response generated through this arm, which is the property that makes STING attractive as a cancer vaccine adjuvant. Evidence source is MODEL_ORGANISM (mouse vaccination and tumor models).
Chronic Type I Interferon-Driven Tissue Inflammation
consequence
When the central effector runs constitutively rather than transiently, sustained type I interferon and interferon-stimulated gene expression become the disease. The clinical expression is organ-specific and set by which tissues signal: small-vessel and acral vasculopathy with endothelial activation and apoptosis, interstitial lung disease and pulmonary fibrosis, inflammatory arthritis, and, where the brain is involved, a calcifying encephalopathy with leukodystrophy. The shared laboratory readout is a peripheral blood interferon signature, which is necessary but not sufficient to place a disorder in this module.
Show evidence (3 references)
"STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173."
Establishes a human disease whose entire phenotype is produced by constitutive activity of this axis. Evidence source is HUMAN_CLINICAL (six patients with clinical, immunologic and genetic characterization).
"We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients."
Confirms the interferon-driven inflammatory phenotype in patients whose lesion is in STING trafficking rather than in STING itself. Evidence source is HUMAN_CLINICAL (symptomatic patient blood).
"Trex1 (-/-) mice develop lethal, IFN-driven autoimmune disease that is dependent on activation of the ISD pathway"
Shows that the chronic inflammatory outcome is pathway-dependent and not merely correlated with it. Evidence source is MODEL_ORGANISM (Trex1-null mice).
Signal-Strength-Dependent Lymphocyte Apoptosis and Regulatory B Cell Induction
counter regulatory
STING is expressed as widely in lymphocytes as in myeloid cells, and in T cells the response is intensified: strong agonist exposure induces a distinct transcriptional program ending in apoptosis rather than activation. In B cells, agonist exposure drives differentiation of IL-35-producing and IL-10-producing regulatory B cells through an IRF3-dependent but type I interferon-independent route, which suppresses natural killer cell proliferation and blunts the antitumor response the therapy was intended to produce. This arm is why systemic, unrestricted STING agonism is self-limiting, and it is the mechanistic content behind the failure of agonist monotherapy in trials; it is not a route to disease in the interferonopathies, where cell-intrinsic constitutive signalling has a different tissue distribution.
Downstream
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Attenuated Antigen Expression and Blunted Adaptive Response
Loss of responding lymphocytes and expansion of regulatory B cells subtract directly from the adaptive response the adjuvant was meant to generate.
Show evidence (3 references)
"Here we show that T cells exhibit an intensified STING response, which leads to the expression of a distinct set of genes and results in the induction of apoptosis."
Establishes the cell-type-dependent bifurcation of the same signal into activation or apoptosis, which is the mechanistic basis for this node. Evidence source is MODEL_ORGANISM (mouse primary and leukaemic T cells).
"Here we show that the administration of five distinct STING agonists, including cGAMP, results in an expansion of human and mouse interleukin (IL)-35+ regulatory B cells in pancreatic cancer."
Documents the regulatory B cell arm as a general consequence of agonist exposure rather than a property of one compound. Evidence source is MODEL_ORGANISM (preclinical cancer models with human and mouse B cells).
"These findings reveal an intrinsic barrier to systemic STING agonist monotherapy and provide a combinatorial strategy to overcome immunosuppression in tumours."
States the therapeutic consequence this node exists to record: the counter-regulatory arm is intrinsic to systemic agonism, not an avoidable side effect of a particular agent. Evidence source is MODEL_ORGANISM.
Suppression of Cap-Dependent mRNA Translation
counter regulatory
STING activation restrains cap-dependent protein synthesis at the level of translation initiation, by at least two routes: an interferon-dependent route requiring IFNAR1 and IRF9, in which interferon-stimulated gene products drive dephosphorylation of 4E-BP1 and so prevent eIF4F assembly and ribosomal loading; and a non-canonical route in which STING at the endoplasmic reticulum directly activates PERK, which phosphorylates eIF2-alpha, ahead of and independently of TBK1-IRF3. The effect is physiologic in antiviral defence, where it restricts production of viral proteins, and adverse in mRNA vaccination, where the antigen is itself an exogenous transcript that must be translated: a codelivered agonist therefore suppresses the antigen it is meant to adjuvant. Timing rather than dose is the operative variable, since translation is spared while the interferon response has not yet been induced.
Downstream
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Attenuated Antigen Expression and Blunted Adaptive Response
Reduced translation of the antigen-encoding transcript lowers the amount of antigen available for presentation.
Show evidence (3 references)
"Using vesicular stomatitis virus as a model, we identified a requirement of STING to inhibit translation during infection and upon transfection of synthetic RLR ligands. This inhibition occurs at the level of translation initiation and restricts the production of viral and host proteins."
Establishes translational suppression as a genuine STING effector function acting at initiation, and shows it is separable from interferon transcription. Evidence source is IN_VITRO (infection and transfection of knockout cell lines).
"Here we identify the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway, a previously unknown cGAS-STING mechanism, enabling an innate immunity control of cap-dependent messenger RNA translation."
Documents the second, interferon-independent route to the same outcome, which matters because blocking interferon signalling does not necessarily restore translation. Evidence source is IN_VITRO.
"The development of cGAS-STING (stimulator of interferon genes) agonists as mRNA vaccine adjuvants has been hampered by widespread STING expression and by the observation that codelivered STING agonists suppress antigen mRNA translation."
States the applied consequence of this node for mRNA vaccine adjuvant design, which is the reason it is modelled separately from the lymphocyte arm. Evidence source is MODEL_ORGANISM (mouse and humanized STING mouse studies).
Attenuated Antigen Expression and Blunted Adaptive Response
consequence
The two counter-regulatory arms converge: less antigen is made, and fewer lymphocytes survive to respond to it, so an agonist added to an mRNA or peptide vaccine can reduce rather than increase antigen-specific T cell output. This node is what a delivery strategy has to defeat, and it is defeated by separation in time and in space rather than by lowering the dose: releasing the agonist only after antigen has been translated, and confining pathway activation to antigen-presenting cells. It has no counterpart in the interferonopathies and should not be conformed to by a genetic disease entry.
Show evidence (1 reference)
"Intratumoral or subcutaneous LNPs are preferentially internalized by myeloid cells, preserving antigen expression fidelity, achieving localized STING activation in antigen-presenting cells and preventing systemic regulatory B cell differentiation and immunocyte apoptosis."
Names both arms this node converges - antigen expression fidelity, and systemic regulatory B cell differentiation with immunocyte apoptosis - but states them as harms a spatially confined delivery strategy averts, not as a measured deficit in an unmodified agonist-adjuvanted vaccine. PARTIAL because the attenuated adaptive output is therefore inferred from what the strategy has to prevent rather than measured directly; the abstract's directly measured translational-suppression sentence is cited on Suppression of Cap-Dependent mRNA Translation instead. Evidence source is MODEL_ORGANISM.
STING Agonist Immunoadjuvant Therapy
Platform:
Small molecule
Pharmacologic agonists occupy the STING ligand-binding domain and switch the axis on deliberately, either intratumorally as an in situ vaccine or codelivered with a defined antigen as a vaccine adjuvant. Cyclic dinucleotides (2'3'-cGAMP and synthetic derivatives) and non-nucleotide agonists (MSA-2 for human STING, the flavonoid DMXAA for mouse STING) are the two chemotypes. This is the module's agonist drug-target pattern; it is a design pattern, not a treatment recommendation, and conforming disorder entries do not inherit it.
Evidence: 1
MSA-2, the compound both evidence items on this treatment actually report, has no CHEBI or NCIT term of its own, so it is recorded against the NCIT drug-class term STING Agonist (NCIT:C176586) with the specific compound named in preferred_term. DMXAA (vadimezan) is retained because the module's HUMAN_MODEL_MISMATCH discussion is about it, but it is mouse-STING-selective and must not be read as the human-active agent; 2'3'-cGAMP is the endogenous cyclic-dinucleotide chemotype.
Janus Kinase Inhibition
Platform:
Small molecule
JAK1/JAK2 inhibitors (baricitinib, ruxolitinib) do not act on STING. They block signalling through the type I interferon receptor downstream of it, and so attenuate the chronic inflammatory consequence arm while leaving the constitutively active receptor in place. This is the clinically established treatment pattern for the STING-driven interferonopathies, and the therapeutic asymmetry is deliberate: no approved agent corrects the upstream lesion.
Evidence: 1