Lipids Meet Immunity: Metabolic Control of cGAS-STING

Abstract

The field of immunometabolism highlights the intricate interplay between immunity and metabolism. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a central component of innate immunity that detects double-stranded DNA (dsDNA) from a range of sources, including pathogenic and host-derived DNA. It is now recognized that the cGAS-STING pathway has broad implications in a variety of human conditions including cancer, age-related diseases, and autoimmune disorders. Given the abundance and diversity of lipids across cellular compartments serving as structural components and signaling molecules, it is unsurprising that lipid metabolism influences the regulation of cGAS-STING signaling. Lipids can directly alter signaling protein dynamics through interactions within membrane compartments, while alterations in lipid metabolism can remodel multiple cell-intrinsic signaling cascades. Here, we summarize emerging concepts and recent discoveries that have advanced our understanding of how lipid metabolism and lipids regulate the cGAS-STING pathway.

1. Introduction

The cGAS-STING pathway is a central component of innate immunity, activated during infection and various forms of cellular stress. Dysregulation of cGAS-STING signaling has been implicated in a broad spectrum of diseases, including cancer, metabolic diseases, immune disorders, and neurodegeneration [1,2,3,4,5,6]. Activation of STING can promote anti-tumor immunity while inhibition of STING can be beneficial in contexts such as autoimmune diseases driven by excessive STING activation. The connection between cGAS-STING signaling and diverse human pathologies is unsurprising, given that the pathway governs inflammation, a fundamental and key process underlying many human diseases [7].

During infection or cellular stress, dsDNA can accumulate in the cytosol [8,9,10]. cGAS binds to the dsDNA and produces cyclic dinucleotides, for example 2′3′-cyclic GMP-AMP (2′3′-cGAMP) [8,9,10]. These cyclic dinucleotides can in turn bind to STING at the endoplasmic reticulum (ER) and trigger trafficking of STING to several other cellular membrane compartments including the Golgi, endosomes, and lysosomes [11,12]. Downstream of STING activation is the induction of type I interferon through interferon regulatory factor 3 (IRF3) and other cytokines through the nuclear factor kappa B (NF-κB) pathway (Figure 1). We refer readers to other extensive reviews which detail the key events of cGAS-STING activation [8,9,10]. As a membrane protein, it is plausible that STING is regulated by the lipid composition of its resident organelles. More broadly, beyond the conventional roles of lipids in directly regulating STING [13,14], changes in lipid metabolism can provide signals that influence the cGAS-STING pathway [15,16]. Likewise, cGAS-STING signaling can, in turn, regulate lipid metabolism [17,18]. The interplay between the cGAS-STING pathway and lipid metabolism exemplifies the integration of metabolism and immune processes, collectively referred to as immunometabolism, an active area of research due to the systemic implications for organismal homeostasis [19,20].

The focus of this review is to examine how lipid metabolism influences the activity of the cGAS-STING pathway. Currently, no unified model explains how lipid metabolism regulates cGAS-STING signaling, even in widely used cell lines such as the HeLa or HEK293T cell lines. Instead, different aspects of lipid metabolism regulating cGAS-STING signaling have been investigated across different cell types and disease settings. Furthermore, organelle composition, lipidome distribution, and the activities of lipid metabolic enzymes vary between cell types. While a comprehensive synthesis of all related studies lies beyond the scope of this review, we highlight key findings that illustrate the interplay between lipid metabolism and cGAS-STING signaling.

According to the LIPID MAPS^® lipidomics classification [22,23], lipids are organized into eight major categories: fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides. Here we discuss how these lipids may influence cGAS-STING signaling (Figure 1,

Table 1. Impact of different lipid classes on cGAS-STING signaling.

Lipid Class	Lipid/Pathway Component	Effect on cGAS-STING Pathway	Mechanism	Experimental Model/Context	References
Fatty acids	Palmitoylation	Activation	STING palmitoylation on Cys88 and Cys91 enables Golgi signaling cluster	Cell models, SAVI mutations	[13]
Fatty acids	Nitro-fatty acids	Inhibition	Nitro-alkylation inhibits STING palmitoylation	Cell models, SAVI mutations	[24]
Fatty acids	Palmitate	Activation	Palmitate exposure induces mitochondrial stress and mtDNA release	Cell models, diet-induced obesity mice	[25]
Glycerophosphpolipids	PI4P	Activation	PI4P binds STING, enriches PI4P-binding proteins, maintains Golgi lipid environment for STING trafficking	Cell model, ARMH3-deficient mice	[26,27]
Glycerophosphpolipids	PI(3,5)P2	Activation	PI(3,5)P2 binds between STING dimers to promote oligomerization during cGAMP-mediated activation of STING	Structural model, cell models, cell-free assays	[28,29]
Sphingolipids	Sphingomyelin	Activation	Supports membrane structural organization to promote clustering and activation	Cell-free assays, cell models	[30,31]
Sphingolipids	D-ceramide-C6	Inhibition	Disrupts Golgi membrane order	Cell model	[13]
Sphingolipids	CerS6-derived ceramide	Activation	Induces mitochondrial pore formation through VDAC1 oligomerization	Cell model, diabetic mice	[32]
Sphingolipids	S1P	Inhibition	Direct binding to STING inhibits activity	Cell model, SPHK2-deficient mice	[33]
Sterols	Cholesterol	Inhibition/Activation	ER cholesterol binding to STING can prevent ER exit, lysosomal cholesterol accumulation can boost STING trafficking	Cell model, NPC1-deficient mice	[14,34]
Glycerolipids	TAG/LDs	Context-dependent modulation	TAG synthesis and LD formation may buffer lipotoxicity and limit mtDNA-driven cGAS activation; LD dynamics may influence STING trafficking though remains unproven	Cell model, steatosis, HFD mice	[35,36,37,38]
Prenol lipids	Prenylation, ubiquinone, dolichol	Unresolved/Potential indirect modulation	Prenylation regulates trafficking, ubiquinone supports mitochondrial energy production, dolichol affects glycosylation	No direct experimental evidence to date
Saccharolipids	Bacterial envelope lipids (e.g., LPS, sulfolipid-1)	Context-dependent modulation	Host-pathogen interactions induce stress that may indirectly modulate cGAS-STING	Infection models	[39,40]
Polyketides	Doxorubicin	Activation	Induces mitochondrial stress and mtDNA release	Cell model, tumor model in mice	[41]
Polyketides	Brefeldin A	Inhibition	Blocks ER-to-Golgi trafficking of STING	Cell model	[42,43]
Polyketides	Bafilomycin A	Activation	Prevents STING lysosomal degradation and prolongs STING responses	Cell model, tumor model in mice	[44]

). The broad range of lipid metabolic alterations capable of modulating STING activity presents valuable therapeutic opportunities, including the potential to enhance STING activation for immunotherapeutic benefits, particularly in cancer.

2. Fatty Acids and cGAS-STING Signaling

De novo fatty acid synthesis is crucial for generating fatty acids of varying lengths and saturation, involving several key enzymes such as ATP citrate lyase (ACLY), acetyl-CoA carboxylases, fatty acid synthase, stearoyl-CoA desaturase 1 and elongase enzymes [45,46]. Fatty acids can also be sourced from lipolysis and cellular uptake [47,48]. These fatty acids can be incorporated into other lipid classes, such as glycerophospholipids, glycerolipids, and sphingolipids [49,50,51], used for energy production through β-oxidation [46], or utilized to modify proteins [52]. Several studies link fatty acids to cGAS-STING signaling, with key examples discussed below.

Perhaps the classical example of fatty acids regulating cGAS-STING is STING palmitoylation [13]. Palmitoylation at Cys88 and Cys91 on STING in the Golgi compartment drives type I interferon responses and viral resistance [13] (Figure 1). Overactive STING mutants underlying STING-associated vasculopathy with onset in infancy (SAVI) similarly rely on palmitoylation for their activity [13]. It is proposed that palmitoylation promotes STING clustering into lipid rafts at the trans-Golgi network (TGN) [13]. At the same time, it is known that nitro fatty acids directly modify and nitro-alkylate STING at these same sites, Cys88 and Cys91, thereby suppressing cGAS-STING signaling [24].

In acute myeloid leukemia (AML) cell lines, loss of fatty acid desaturase 1 (FADS1), primarily an ER-localized enzyme that introduces double bonds into fatty acids, triggers cell death [53]. FADS1 loss induces lipidomic changes that activate the cGAS-STING pathway [53]. The heightened inflammatory response suggests FADS1 loss may promote anti-leukemic effects through STING activation [53]. In support of this, concomitant STING deletion diminishes AML cell killing by the FADS1 inhibitor, CP-24879, compared to FADS1 inhibition alone [53]. The precise mechanisms by which FADS1 inhibition and associated lipidomic changes enhance cGAS-STING activity remain unclear.

The in vivo relevance of fatty acid synthesis to cGAS-STING activation is underscored by ACLY inhibition, a key strategy often explored in cancer metabolism [49,54]. ACLY inhibition in Pan02, B16 and Hepa1-6 cancer cells increases STING signaling [55]. This stems from polyunsaturated fatty acid accumulation due to increased uptake, leading to lipid peroxidation, mitochondrial damage, and mitochondrial DNA (mtDNA) release that activates cGAS [55] (Figure 1). Notably, combining ACLY inhibition enhances anti-programmed death-ligand 1 (PD-L1) efficacy in mouse models of liver, pancreatic, and melanoma cancers, highlighting a potential therapeutic avenue [55,56]. While ACLY inhibitors have been investigated in a variety of disease settings including liver cancer [57] and dyslipidemia [58], the involvement of cGAS-STING signaling across broader ACLY-targeted contexts remains unexplored.

Fatty acids also link to STING in obesity, often characterized by a hyperlipidemia state. Palmitate treatment has been shown to activate STING signaling in human aortic endothelial cells by elevating leakage of mtDNA into the cytosol [25]. Interestingly, STING-driven activation of the IRF3 transcription factor induces the expression of intercellular adhesion molecule 1 (ICAM-1), thereby facilitating inflammatory cell adhesion to the endothelium [25]. When considering the relevance in vivo, mice fed a high-fat diet (HFD) exhibit elevated phosphorylated IRF3 and ICAM-1 expression in epididymal adipose tissue and aortic walls, however both are attenuated in STING-deficient mice [25]. In addition to that, STING-deficient mice have lower body weight, improved glucose tolerance and insulin sensitivity, and reduced adipose tissue inflammation compared to wild type (WT) mice [25]. These findings position STING as a promising target for mitigating obesity-associated cardiovascular pathophysiology.

Collectively, these studies demonstrate that fatty acids regulate the cGAS-STING pathway through both direct mechanisms, such as STING palmitoylation and indirect mechanisms, including mitochondrial stress and mtDNA release. Notably, perturbation of fatty acid metabolic enzymes can rewire cell-intrinsic pathways, positioning lipid metabolism as an upstream determinant of innate immune activation. As additional enzymes involved in fatty acid metabolism are implicated in disease, further mechanisms linking lipid metabolic dysregulation to cGAS-STING signaling are likely to emerge. Key unanswered questions include how fatty acid composition and metabolic rewiring in disease states shape cGAS-STING activation, and how these changes give rise to distinct molecular and inflammatory outputs.

3. Glycerophospholipids and cGAS-STING Signaling

Glycerophospholipids constitute the primary membrane phospholipids in animal cells, comprising a glycerol backbone esterified to two fatty acyl chains and a phosphate-containing headgroup [59,60]. Cells generate diverse glycerophospholipids by varying the fatty acids and headgroups attached to the phosphate [59,60]. Beyond their canonical roles in membrane architecture and fluidity, their headgroup diversity enables additional signaling functions. For instance, phosphatidylinositol serves as the precursor for phosphoinositides (PIPs), generated via phosphorylation at the 3′, 4′, and/or 5′ positions of the inositol ring [61,62,63]. This structural diversity allows PIPs to function as spatially restricted regulators of cellular signaling [61,62,63]. A notable example among PIP molecules in signaling is Akt activation by phosphatidylinositol (3,4,5)-trisphosphate [64,65]. Multiple studies have implicated phosphatidylinositol 4-phosphate (PI4P) in the control of STING activation and trafficking, particularly at the Golgi where PI4P is abundant [26,27,66,67,68,69,70].

In the Ras-related protein Rab-22A (RAB22A)-mediated non-canonical autophagy pathway, activated STING evades lysosomal degradation by release into extracellular vesicles [71]. RAB22A-positive non-canonical autophagosomes fuse with early endosomes to form a compartment termed the Rafeesome [71]. RAB22A inhibits Ras-related protein Rab-7a, which prevents Rafeesome lysosomal fusion and enables STING secretion in extracellular vesicles to induce interferon β expression in recipient cells of the tumor microenvironment [71]. Inhibition of PI4P generation either by targeting phosphatidylinositol-4-phosphatase (via SAC1) to RAB22A-positive endosomes or depletion of phosphatidylinositol 4-kinase type 2-α impairs Rafeesome formation, supporting PI4P as an effector facilitating STING entry into Rafeesomes [71].

A CRISPRi screen identified Golgi resident protein GCP60 (ACBD3) as essential for STING signaling via phosphatidylinositol 4-kinase beta (PI4KB) [26]. One proposed model is that ACBD3 recruits PI4KB to the TGN to maintain a PI4P-enriched environment for STING activation [26] (Figure 1). Modulating PI4P levels by altering the expression of oxysterol-binding protein or expressing TGN-retained SAC1 fine-tunes STING activity [26]. Moreover, STING directly interacts with PI4P via positively charged residues on its α3 helix (Arg281, Arg284, Lys289, Arg293), and mutation of these residues abolishes the activation of a constitutively active SAVI variant of STING [21,26], reaffirming a role for PI4P in direct STING regulation. Armadillo-like helical domain-containing protein 3 (ARMH3) provides another Golgi-resident link as it binds activated STING post-ER exit and recruits PI4KB for localized PI4P synthesis [27] (Figure 1). This facilitates anterograde transport of STING from the TGN to the endosomes mediated by PI4P-binding proteins, adaptor protein complex 1 and Golgi-localized gamma ear-containing ARF-binding protein 2 [27]. PI4P-interacting factors further integrate glycerophospholipid regulation with broader lipid homeostasis across ER-Golgi-endosome interfaces [72,73,74,75].

Two independent groups recently identified phosphatidylinositol 3,5-bisphosphate (PI(3,5)P₂) as a key regulator of STING activation and trafficking [28,29]. Notably, components of the 1-phosphatidylinositol 3-phosphate 5-kinase (PIKFYVE) complex were found to associate constitutively with STING [28,29]. These studies proposed that low levels of PI(3,5)P₂ generated by the PIKFYVE complex at the ER facilitates efficient STING trafficking from the ER to the TGN upon cGAMP binding and also drives TANK-binding kinase 1 (TBK1) autophosphorylation [28,29]. Structural and biochemical analyses further revealed that both PI(3,5)P₂ and the cholesterol analogue, cholesteryl hemisuccinate, can bind STING in an interdependent manner and act cooperatively to promote STING oligomerization [28,29]. Consistent with the structural and biochemical findings, mutation of STING residues Lys20, Arg71, Ser80 and Trp82, located around the PI(3,5)P₂ and cholesteryl hemisuccinate binding sites, impaired STING trafficking and downstream signaling [28,29]. The PI(3,5)P₂ binding site is also situated between two STING dimers, supporting a model whereby PI(3,5)P₂ functions as a molecular glue, stabilizing STING dimers during cGAMP-induced STING oligomerization at the ER [28,29].

These studies highlight phosphoinositides as a key subgroup of glycerophospholipids that coordinate STING activation through both direct lipid-protein interactions and the regulation of intracellular trafficking machinery. Moreover, phosphoinositides provide a mechanistic link between STING signaling and a broader network of organelle homeostasis regulators. Beyond STING, phosphoinositides also regulate Golgi/TGN organization, ER-Golgi membrane contact sites, and non-vesicular lipid exchange, suggesting that STING may be integrated with organellar lipid composition for precise signaling [63,76,77,78,79]. In this context, ER-Golgi membrane contact sites, Golgi quality control mechanisms, Golgi structural integrity, and lipid exchange pathways may represent important regulatory platforms for controlling STING activation and trafficking, although their precise contributions to STING biology remain to be fully defined.

4. Sphingolipids and cGAS-STING Signaling

Sphingolipids, a diverse class of lipids characterized by a sphingoid base backbone, have emerged as important, direct regulators of the cGAS-STING pathway. Sphingolipids such as sphingomyelin, ceramides, and sphingosine-1-phosphate (S1P) function as potent bioactive signaling molecules [80]. Sphingolipid metabolism is compartmentalized within the cell in a manner that mirrors the trafficking itinerary of STING: synthesis begins in the ER (ceramides), maturation occurs in the Golgi (sphingomyelin), and degradation/recycling takes place in the lysosome [81,82]. This spatial overlap positions sphingolipid metabolism as a checkpoint, coupling STING signaling dynamics to organelle homeostasis [83].

The TGN features sphingomyelin- and cholesterol-enriched lipid rafts [84,85]. In cell-free assays using microsomal membranes to mimic Golgi membranes, STING phosphorylation at Ser365 is markedly dependent on the presence of sphingomyelin [31]. Indeed, enzymatic depletion of sphingomyelin (via sphingomyelinase) or cholesterol (via methyl-beta-cyclodextrin, MβCD) suppresses STING activation, supporting a model whereby sphingomyelin and cholesterol function synergistically to form ordered lipid domains that cluster STING oligomers [31]. This clustering is hypothesized to increase the local concentration of recruited TBK1, facilitating its autophosphorylation and the subsequent activation of STING [30,31]. Disruption of Golgi lipid order by D-ceramide-C6 or 25-hydroxycholesterol breaks this feed-forward activation of STING, rendering STING signaling-incompetent even if it physically reaches the Golgi [13,30]. The physiological importance of this Golgi checkpoint is further underscored by the fact that retrograde transport of STING (from Golgi back to ER) acts as an off-switch to terminate signaling [12,86,87].

Conversely, sphingolipids can also function as potent negative regulators of the cGAS-STING pathway. S1P, generated predominantly by sphingosine kinase 2 (SPHK2), acts as a brake to prevent excessive inflammation during acute lung injury [33]. In murine models of lung injury, S1P produced by CD11b+ macrophages suppresses STING signaling in alveolar macrophages to resolve inflammatory damage [33] (Figure 1). Adoptive transfer of Sphk2-deficient bone marrow monocytes results in persistent lung inflammation during vascular injury in CD11b+ macrophage depleted mice [33]. Beyond this paracrine role, S1P directly binds STING, as co-immunoprecipitation shows S1P-STING complex formation in macrophages and molecular docking suggests that S1P can associate with the C-terminal domain of STING, potentially engaging the canonical ligand-binding pocket and/or an additional allosteric site [33].

Ceramide, the precursor of sphingomyelin, can also trigger cGAS activation during sterile inflammation [32]. In mouse models of glomerular injury and human glomerular disease, ceramide synthase 6 (CerS6) expression is upregulated in podocytes [32]. Podocyte-specific CerS6 knockout ameliorates glomerular injury and inflammation, while CerS6 overexpression drives podocyte damage through mtDNA release and cGAS-STING activation [32]. Mechanistically, CerS6-derived ceramide (d18:1/16:0) binds voltage-dependent anion channel 1 (VDAC1) at Glu59, promoting VDAC1 oligomerization and mitochondrial pores that permit mtDNA leakage into the cytosol [32] (Figure 1). The link between ceramide, mtDNA and cGAS-STING axis has also been studied in ischemia [88]. Serine palmitoyltransferase 2 (SPTLC2), the rate-limiting enzyme in de novo ceramide synthesis, is essential for cGAS-STING activation in astrocytes and brain tissue during ischemia, as Sptlc2 deficiency blocks interferon responses and attenuates inflammatory damage [88].

Canonical sphingolipids contain a sphingosine backbone synthesized from serine and palmitoyl-CoA by serine palmitoyltransferase (SPT). However, under serine deprivation, a condition common in the nutrient-poor core of solid tumors, SPT becomes promiscuous and utilizes alanine instead, yielding non-canonical 1-deoxysphingolipids (deoxySLs) [89,90]. In colon cancer cells, serine deprivation increases deoxySLs, which drive mitochondrial dysfunction, mtDNA release into the cytosol, and subsequent cGAS-STING activation [91] (Figure 1). Direct administration of deoxySLs or use of alanine-preferring SPT mutants similarly induces cGAS-STING signaling and type I interferon responses [91]. In colorectal tumor models, elevating deoxySLs (via SPT mutation or alanine-enriched diets) suppresses tumor growth through cGAS-STING-dependent infiltration of activated dendritic cells and cytotoxic T cells [91].

Sphingolipids exert dual roles in cGAS-STING signaling, for instance acting as structural enablers of STING at the Golgi (e.g., sphingomyelin in lipid rafts) and negative regulators that can restrict excessive STING signaling (e.g., S1P). This duality underscores sphingolipid metabolism as a rheostat rather than a simple on-off switch for innate immune signaling. How cells coordinate sphingolipid interconversion, trafficking, and compartmentalization to balance activation versus suppression, and whether specific sphingolipid species preferentially engage STING or its regulators, remain to be elucidated.

5. Sterols and cGAS-STING Signaling

Sterols are typically recognized by their four-fused ring structure, with cholesterol being the most represented sterol in animals. Cholesterol is often found in lipid bilayers and, as cholesterol esters, in lipoproteins and lipid droplets (LDs). On the other hand, oxysterols are far less abundant than cholesterol in humans and are best known for binding to the liver X receptor (LXR) and nuclear receptor retinoid-related orphan receptor to regulate immune cell function and cholesterol export [92]. The ER is the site of cholesterol synthesis, where sterol levels modulate levels of ER proteins such as cholesterol biosynthesis enzymes and regulate the transcriptional activity of sterol regulatory element-binding protein 2 (SREBP2) [93,94,95,96,97,98,99].

In THP1 cells, cGAMP reduces ER cholesterol levels, with cholesterol removal being mediated by sterol O-acyltransferase 1 (SOAT1) [14]. Consequently, loss of SOAT1 maintains cholesterol levels in the ER and dampens STING activation [14]. In contrast, exposing THP1 cells to cGAMP and MβCD (to deplete cholesterol) enhances the STING pathway responses compared to cGAMP alone [14]. These observations support the notion that reduced ER cholesterol facilitates STING signaling. In mice, MβCD alone could prime the STING pathway in response to what are likely low levels of intrinsic signals that activate STING [14]. Furthermore, combining MβCD with cGAMP could improve anti-tumor effects in a solid-flank tumor mouse model [14]. As an ER-resident protein, it is plausible that STING can sense ER cholesterol via its cholesterol recognition/interaction amino acid consensus (CRAC) motif [14,100]. Mutation of the inverted CRAC motifs (Figure 1) in STING promotes STING ER exit, reinforcing cholesterol’s role in regulating STING dynamics through direct binding [14].

The link between cholesterol metabolism and STING signaling has also been explored with genetic manipulation of SREBP2, the master transcription factor required for cholesterol synthesis. In both primary human peripheral blood mononuclear cell-derived macrophages and THP1 cells, SREBP2 loss triggers basal IFNB1 and interferon-stimulated gene (ISG) signatures [101] (Figure 1). The significance of SREBP2 in enabling ISG signatures extends to mouse embryonic fibroblasts which are non-immune cells [101]. There is also upregulated type I interferon response when flux through the cholesterol synthesis pathway is reduced, as evident in primary fibroblasts of an individual with mevalonate kinase deficiency and macrophages with silenced mevalonate kinase or HMGCR expression [101]. In the context of Niemann-Pick disease type C (NPC), the NPC1 protein interacts with STING to promote lysosomal degradation; NPC1-deficiency spares STING while lowering ER cholesterol and accumulating lysosomal cholesterol [34]. Consequently, SREBP2 traffics from the ER to the Golgi to increase cholesterol synthesis and intriguingly, STING is primed for activation as its trafficking to the Golgi is coupled to SREBP2 trafficking [34]. These observations suggest that reduced ER cholesterol pools can trigger spontaneous STING activation [34,101].

LXRα and LXRβ are key transcriptional regulators of lipid homeostasis, activated by ligands including oxysterols [102]. The LXR agonist T0901317 inhibits cGAMP-mediated activation of cGAS-STING signaling by upregulating sphingomyelin phosphodiesterase acid like 3A (SMPDL3A), which hydrolyzes cGAMP [15] (Figure 1). In mice, T0901317 increases susceptibility to herpes simplex virus 1 (HSV-1) infection, suggesting restriction of STING signaling potentially through SMPDL3A [15]. Consistent with this, the effect is abolished in Smpdl3a knockout mice [15]. It is worth noting that endogenous oxysterols and LXR have a historical connection to the development of vascular diseases [103,104,105], but their interplay with the cGAS-STING pathway in STING-relevant vascular diseases awaits further discovery [106,107].

Genetic and pharmacological perturbations of cholesterol biosynthesis exert substantial control over STING activation, in part by altering ER cholesterol content and thereby regulating STING retention versus release. Beyond cholesterol and oxysterols, the cholesterol synthesis pathway generates multiple intermediate sterols that may also influence cGAS-STING signaling, although evidence remains limited. Sterol intermediates can accumulate in certain biological contexts, with documented roles in diverse biological processes and disease [108,109,110,111,112]. For example, lanosterol accumulation can reduce ISG expression [109] and 7-dehydrocholesterol can promote IRF3 phosphorylation and enhance type I interferon production [111]. Together, these observations raise the possibility that flux through the cholesterol biosynthesis pathway, rather than cholesterol abundance alone, shapes cGAS-STING signaling. Defining how distinct sterol intermediates influence STING activation, trafficking, or termination represents an avenue for future investigation.

6. Glycerolipids and cGAS-STING Signaling

Glycerolipids are built on a glycerol-3-phosphate backbone with varying numbers of fatty acids that can be attached [113]. The best-known glycerolipids are triacylglycerols (TAG), which are the most abundant storage lipids commonly found in LDs [113,114]. While studies remain limited, emerging evidence suggests that TAGs can regulate cGAS-STING signaling.

One study found that fatty acid synthesis controls ISG expression and type I interferon responses in CD4⁺ T cells through cGAS-STING [35]. Subsequently, it was shown that stearoyl-coenzyme A desaturase 2 (SCD2) deletion in Th1 cells increased cGAMP levels and cytosolic accumulation of genomic DNA [35]. SCD2 catalyzes the conversion of saturated fatty acids into monounsaturated fatty acids (MUFAs) and SCD2-deficient Th1 cells showed reduced oleate-containing TAGs (e.g., 16:0/18:0/18:1, 16:0/16:0/18:1, 16:0/18:1/18:1) [35]. Notably, blocking glycerolipid synthesis (via glycerol-3-phosphate acyltransferase 1 deletion) or TAG synthesis (via diacylglycerol O-acyltransferase 1 deletion) likewise induced ISGs [35].

HFD-induced nonalcoholic steatohepatitis (NASH) causes liver steatosis, ballooning, and fibrosis, but these phenotypes are attenuated in STING-deficient mice [36]. These mice also showed reduced cholesterol, triacylglycerols, and low-density lipoproteins when compared to HFD-fed WT control mice [36]. While hepatocytes from HFD-fed mice lack STING expression based on antibody-based detection, the Kupffer cells robustly express STING [36]. These Kupffer cells exhibit an elevated NF-κB response when exposed to mtDNA derived from hepatocytes of HFD-fed mice compared to those from chow-fed controls [36]. Although it remains unclear whether TAGs and their biosynthetic enzymes directly regulate cGAS-STING in NASH, lipid overload unequivocally induces cellular stresses that trigger mtDNA release [36,37,115].

Glycerolipids, particularly TAGs in LDs, appear to influence cGAS-STING signaling primarily through indirect mechanisms that mitigate lipotoxicity, restraining mitochondrial stress and limiting mtDNA release. An indirect link between STING trafficking and LD dynamics has recently emerged through genetic deletion of ancient ubiquitous protein 1, a protein that localizes to both the ER and LDs, and regulates lipid abundance alongside STING trafficking [38]. Given that the ER is the central hub for both STING residence and LD biogenesis [116,117], these findings suggest a previously underappreciated interface between neutral lipid homeostasis and innate immune signaling. Moving forward, systematic interrogation of LD dynamics, glycerolipid flux, and lipase activity during cGAS-STING activation will be critical for defining whether glycerolipid metabolism acts merely as a protective buffer or instead constitutes an active regulatory layer of the cGAS-STING pathway.

7. Prenol Lipids in cGAS-STING Signaling

In mammals, prenol lipids are derived from five-carbon isoprene units which are produced by the mevalonate pathway [118]. Key examples of human-synthesized prenols include ubiquinone (coenzyme Q), vitamin K, squalene, and dolichols, while others such as vitamins A and E are acquired dietary prenols [95,118,119,120,121]. To date, no robust evidence indicates that prenol lipids directly modulate cGAS-STING activity. However, established roles of certain prenol lipids in key biological processes suggest potential indirect regulation of cGAS-STING signaling, though this requires experimental validation. Ubiquinone serves as a critical component of the mitochondrial electron transport chain [122]. Given the established role of mitochondrial stress, reactive oxygen species, and mtDNA release in cGAS activation, alterations in ubiquinone availability or function could indirectly affect cGAS activation. Dolichol is a lipid involved in protein glycosylation at the ER, a process essential for protein folding, quality control and secretory pathway function [123]. As STING resides in the ER at steady state and undergoes tightly regulated ER-to-Golgi trafficking upon activation, perturbations in ER proteostasis or glycosylation capacity may influence STING trafficking or turnover. Notably, prenol lipid biosynthesis remains incompletely characterized. In fact, recent progress mapping the terminal steps of dolichol synthesis has linked defects in this pathway to a rare congenital disorder of glycosylation [120,124], underscoring how gaps in metabolic annotation can obscure connections between lipid metabolism and cellular signaling.

Among prenol-dependent processes, protein prenylation represents the most direct potential interface with STING regulation. Prenylation, which relies on geranylgeranyl pyrophosphate or farnesyl pyrophosphate, is essential for the localization and trafficking of numerous proteins, including small GTPases [125,126]. Given that STING trafficking constitutes a key regulatory checkpoint in pathway activation and termination [12,83], the availability of prenol lipids for protein prenylation is likely to fine-tune STING signaling outputs. Although direct experimental evidence remains limited, prenol lipid metabolism represents a largely unexplored regulatory layer with potential implications for innate immunity and disease-associated signaling states.

8. Saccharolipids in cGAS-STING Signaling

Saccharolipids feature lipid moieties anchored to sugar backbones, with lipid A from lipopolysaccharide (LPS) on the outer membrane of Gram-negative bacteria serving as the archetypal example [127,128]. Other saccharolipids, such as trehalose dimycolate and sulfolipid-1, underpin mycobacterium functions [129,130,131]. Unlike other lipid classes discussed in this review, classical saccharolipids like lipid A are synthesized exclusively via prokaryotic biosynthetic routes [128,132], and therefore do not function as intrinsic regulators of cGAS-STING signaling in human cells. Instead, saccharolipids act as exogenous microbe-associated molecular patterns [132] that may shape host–pathogen interactions and indirectly influence cGAS-STING activation. For example, LPS-induced acute lung injury has been reported to increase STING levels in murine lung tissue [39]. In the context of Mycobacterium tuberculosis infection, bacterial mechanisms that impair host DNA repair promote cGAS-STING activation, releasing type I interferons while concomitant expansion of host LDs supports pathogen survival [40]. It is therefore plausible that the specific saccharolipid composition on the lipid-rich envelope of Mycobacterium tuberculosis contributes to the cellular context in which cGAS-STING signaling is engaged, although the molecular details of such interactions remain undefined.

Collectively, saccharolipids differ fundamentally from the other lipid classes discussed in this review in that they are intrinsic components of microbial pathogens and are therefore primarily engaged in host–pathogen interactions rather than cell-intrinsic lipid metabolism. As structural constituents of bacterial envelopes, saccharolipids are integral to the infection process itself and can indirectly shape the cellular context in which cGAS-STING signaling occurs [128,131,133]. In this regard, the nature of saccharolipids may favor microbe survival rather than host defense, although the precise balance and interactions still need further study. An important unresolved question is whether distinct saccharolipid structures selectively bias cGAS-STING activity relative to other inflammatory pathways, thereby contributing to heterogeneous host responses across infections.

9. Polyketides in cGAS-STING Signaling

Polyketides are not synthesized by humans; rather, they represent secondary metabolites produced by microbes via modular polyketide synthases [134,135]. Well-known polyketides include clinically important antibiotics (e.g., erythromycin, tetracycline, rapamycin), antifungals (e.g., amphotericin B), anticancer agents (e.g., doxorubicin), and statins (e.g., lovastatin), all of which are derived from bacteria or fungi [136,137,138,139,140]. Despite their structural diversity and clinical importance, evidence for direct regulation of cGAS-STING signaling by polyketides remains limited. The best-characterized links involve indirect mechanisms. Doxorubicin promotes the release of oxidized mtDNA from tumor cells and its transfer to antigen-presenting cells, thereby activating cGAS-STING [41]. Additionally, lovastatin induces mitochondrial stress in colorectal cancer cells, triggering mtDNA release and subsequent cGAS-STING pathway activation [141]. Other polyketides function as experimental tools that overlap with STING regulation. Brefeldin A is a fungal polyketide used to block ER-to-Golgi trafficking [142,143], thus impairing STING trafficking and downstream signaling [42,43]. Bafilomycin A1 impairs endolysosomal acidification, preventing STING degradation and enhancing STING-dependent anti-tumor immune responses [44].

To date, direct regulation of cGAS-STING by polyketides (e.g., binding to cGAS or STING, or via a defined lipid-like post-translational modification) has not, to our knowledge, been demonstrated. Instead, available evidence supports a model in which select polyketides act as pharmacological modulators that influence cGAS-STING activity indirectly by inducing mitochondrial stress or perturbing intracellular trafficking. As such, polyketides are best viewed not as physiological lipid regulators, but as exogenous compounds that can experimentally or therapeutically reshape cGAS-STING signaling, with broader implications for immunometabolism and treatment response.

10. Therapeutic Implications of Lipid Regulation of cGAS-STING

Both the cGAS-STING pathway and lipid metabolism have emerged as central areas of investigation across a wide range of major human diseases, including metabolic disorders, cancer, neurodegenerative diseases, and autoimmune conditions [1,2,3,6,144,145,146,147]. Given the extensive lipid-dependent regulatory checkpoints governing cGAS-STING signaling, dysregulated lipid metabolism may represent a key determinant of aberrant pathway activity in disease. While current therapeutic strategies primarily target cGAS or STING directly due to their DNA-sensing pathway specificity [148,149,150], lipid metabolism encompasses a broader and pharmacologically rich landscape of enzymatic targets. Modulation of lipid metabolic pathways therefore represents an attractive and potentially complementary approach for tuning cGAS-STING signaling in pathological contexts.

In Parkinson’s disease, multiple studies have reported widespread alterations in the lipidome, including changes in sphingolipids, glycerophospholipids, and glycerolipids [151,152,153]. Given the sensitivity of STING activation and intracellular trafficking to the lipid environment across multiple organelles, it is plausible that lipid metabolic dysfunction in Parkinson’s disease perturbs organelle homeostasis in ways that influence cGAS-STING signaling. In support of this, region-specific lipid changes within the brains of Parkinson’s disease patients have been correlated with mitochondrial dysfunction [151] and aberrant activation of cGAS-STING has been reported in microglia and neurons [4,154,155]. However, the extent to which disease-associated lipid dysregulation directly contributes to pathological cGAS-STING activation remains poorly defined. Identifying lipid metabolic pathways that intersect with STING activation in Parkinson’s disease may reveal new opportunities for therapeutic intervention.

Lysosomal storage disorders (LSDs) such as Gaucher disease and Sandhoff disease provide more direct evidence linking lipid metabolism dysfunction to intrinsic cGAS-STING activation [34,156,157]. In Gaucher disease, glucocerebrosidase deficiency leads to accumulation of glucosylceramide [157,158]. Glucosylceramide accumulation has been shown to promote mitochondrial dysfunction and mtDNA release, leading to neuroinflammation in microglia driven by cGAS-STING [159]. In mouse models of glucocerebrosidase deficiency, limiting STING activity ameliorates neuroinflammatory and neurodegenerative phenotypes [159]. Similarly, Sandhoff disease, characterized by accumulation of GM2 gangliosides due to hexosaminidase B deficiency, exhibits constitutive STING activation and STING deletion improves motor outcomes in mouse models [156]. More broadly, neuronal cell models carrying distinct genetic disruption of LSD-associated proteins, including cathepsin D, glucocerebrosidase, and NPC1, converge on cGAS-STING activation as a shared phenotype [156]. These findings suggest that therapeutic modulation of lysosomal lipid metabolism in select LSDs, alone or in combination with cGAS-STING modulation may represent a viable strategy to attenuate inflammation.

In cancer, cGAS-STING signaling plays a dual role, promoting anti-tumor immunity through type I interferon responses, while also contributing to tumor-promoting inflammation in certain contexts [160]. Importantly, many cancers undergo profound lipid metabolism reprogramming during disease progression [161], which is likely to reshape cGAS-STING signaling in a lipid-dependent manner. Consistent with this idea, inhibition of lipid metabolic enzymes such as ACLY has been shown to enhance responses to immune checkpoint blockade (e.g., anti-PD-L1 therapy) [55,162,163]. In addition, cholesterol synthesis inhibition with lovastatin combined with radiotherapy enhances anti-tumor immunity through cGAS-STING [164]. These studies provide a strong rationale for exploring lipid-targeting strategies as means to optimize STING-based cancer immunotherapies.

Collectively, these observations reveal immunometabolism as a unifying feature of multiple human diseases [3,45,145,165,166]. Several STING agonists and antagonists have entered preclinical and early clinical development, particularly in oncology and inflammatory disease settings [149,150,167]. While direct modulation of STING can elicit potent immune responses, clinical translation has been challenged by issues including therapeutic window, resistance, and context-dependent outcomes of STING targeting [150,168]. These limitations highlight the need for alternative strategies that enable more graded control of pathway activity. Therapeutically, this raises the possibility that reprogramming lipid metabolism could be used to fine-tune cGAS-STING activity, either to dampen chronic inflammation in neurodegenerative and autoimmune diseases or to potentiate immune activation in cancer. Such combination strategies may ultimately enable more precise and context-dependent modulation of innate immune responses than direct pathway targeting alone.

11. Conclusions and Future Directions

Accumulating evidence positions lipid metabolism as a central regulator of cGAS-STING signaling, acting through diverse interconnected mechanisms. Across lipid classes, regulation converges on a few core principles: lipid-dependent modulation of STING activity, control of STING localization through membrane and organelle homeostasis, and indirect activation of cGAS via mitochondrial stress and mtDNA release. Several fundamental questions remain unresolved. These include whether additional lipid species directly engage cGAS or STING, how metabolic flux through lipid pathways shapes signaling kinetics, and how activating versus inhibitory lipid cues are integrated within individual cells. Moreover, the specificity of lipid-mediated regulation for cGAS-STING versus other innate immune pathways remains poorly defined. Systematic integration of lipidomics, spatially resolved biology, and in vivo disease models will be critical to resolve these questions.

From a translational perspective, dysregulated lipid metabolism intersects with aberrant cGAS-STING activity in cancer, metabolic disease, neurodegeneration, cardiovascular disorders, and LSDs. Modulating lipid metabolic enzymes, organelle lipid composition, or lipid-dependent regulation checkpoints offers the potential to fine-tune innate immunity, either to amplify anti-tumor immunity or restrain chronic inflammation. In summary, these insights exemplify broader principles of immunometabolism, illustrating how metabolic state, organelle homeostasis, and innate immune sensing are fundamentally intertwined. Future studies that leverage this understanding to develop context-specific interventions could unlock the full therapeutic potential of the cGAS-STING pathway.