English

• 1. Introduction

  Cholesterol metabolism and innate immunity are deeply interlinked, with cholesterol playing a vital role in modulating immune functions. Along with other lipids like triglycerides and phospholipids, cholesterol is crucial for maintaining cellular energy balance and facilitating immune responses. Specifically, cholesterol-rich lipid rafts within cell membranes organize receptors and signaling molecules essential for immune activation, including Toll-like receptor (TLR) signaling. This influence of cholesterol metabolism on immune function extends to various diseases, notably cancer, where abnormal cholesterol levels fuel tumor growth and enable immune evasion. In the tumor microenvironment (TME), elevated cholesterol levels can polarize tumor-associated macrophages (TAMs) toward an immunosuppressive phenotype, promoting tumor progression. Moreover, cholesterol plays a significant role in regulating the stimulator of interferon genes (STING) pathway, which is critical for innate immunity and anti-tumor responses. Reduced cholesterol levels in the endoplasmic reticulum (ER) facilitate STING pathway activation, boosting the immune response against tumors. Conversely, elevated cholesterol levels inhibit STING pathway activation, allowing tumors to escape immune detection. These findings highlight cholesterol metabolism as a valuable therapeutic target for restoring effective immune responses in cancer; however, the high doses required to achieve immune-regulating effects limit its druggability in clinical practice. nanoparticles (NPs) may solve offer an innovative delivery system for cholesterol-lowering agents, providing benefits such as targeted delivery, enhanced bioavailability, and controlled release. Additionally, they can co-deliver STING agonists, enabling precise immune modulation and reducing the risk of chronic inflammation. This review examines the potential of combining cholesterol-lowering approaches with NPs technology to activate the STING pathway and improve outcomes in cancer immunotherapy.

  2. STING pathway: A new frontier in cancer immunotherapy

  The relationship between cancer and the immune system has been a subject of research for more than a century, initially observed by Rudolph Virchow [1]. The immune system is essential for detecting and eradicating pathogens and malignant cells by identifying non-self-antigens. This process includes recognizing foreign or abnormal cells, activating effector functions to eliminate them, and developing immune memory to safeguard against future threats [2,3]. In the context of cancer, this defense mechanism is known as cancer immunoediting and consists of three stages: eradication, equilibrium and escape. In the elimination phase, the immune system recognizes and destroys cancer cells. The equilibrium phase is a period during which the immune system controls the growth of cancer cells, keeping them in a dormant state. During the escape phase, cancer cells develop mechanisms to avoid detection by the immune system, leading to tumor progression. This ability to evade the immune system is an important sign of cancer progression [3].

  Current cancer immunotherapy strategies include immune checkpoint inhibitors (ICIs), chimeric antigen receptor T (CAR-T) cell therapy, and cancer vaccines. For example, ICIs, such as programmed death-1 (PD-1) antibodies, work by blocking inhibitory signals that prevent immune cells from targeting cancer cells. In contrast, CAR-T cell therapy involves modifying T cells to more effectively recognize and destroy cancer cells [4]. Although immunotherapy shows considerable potential, challenges like resistance, patient variability, and immune-related side effects remain, emphasizing the necessity for continued research to optimize these treatments. Table S1 (Supporting information) [5–11] provides a summary of various immunotherapy categories, target proteins, approved drugs, and relevant indications derived from multiple clinical trials.

  Despite the advancements in cancer immunotherapy, challenges such as treatment resistance, immune-related side effects, high costs, and limited efficacy in solid tumors underscore the need for novel approaches like STING pathway activation, which enhances anti-tumor immunity and addresses immune suppression within the tumor. For details, please refer to Supporting information 1.1 [12–14].

  2.1 STING: providing new potential in immune activation

  To further explore the connection between cholesterol metabolism and immune response, we discuss the STING pathway, a central mechanism in innate immunity that has emerged as a promising new target in tumor immunotherapy [15]. For details, please refer to Supporting information 1.2 [16–23].

  The activation of the cyclic GMP-AMP synthase (cGAS)-STING pathway is pivotal in both immune cells and tumor cells, serving as an innate immune sensor that can modify diverse stages of the tumor-immunity cycle. This mechanism of cytosolic DNA sensing is well-documented for its ability to induce interferon (IFN) production and stimulate immune responses through the infiltration of immune cells [24]. Activation of the cGAS-STING pathway in tumor cells can inhibit early neoplastic cells by upregulating IFN-Ⅰ or other inflammatory genes (Fig. 1). Notably, this pathway is also strongly associated with the induction of cancer cell senescence [25], thereby mediating tumor-suppressive effects. The ability of cGAS-STING pathway to induce senescence relies on the secretion of proteases, growth factors, chemokines, and pro-inflammatory cytokines, which collectively constitute the senescence-associated secretory phenotype (SASP) [25]. These immune-stimulatory factors can result in tumor control directly within tumor cells or by activating immune cells to target cancers [26]. Thus, STING activation propagates the cancer-immunity cycle and remodels the TME. The immunomodulatory effects of STING also make it an appealing target for cancer immunotherapy.

  Figure 1

  

  Figure 1.  The diagram shows the process of the cGAS-STING pathway. When DNA from infections, cell stress, or tumors enters the cytoplasm, it activates the enzyme cGAS. cGAS then produces cGAMP, which binds to STING protein in the ER. STING moves to the Golgi and triggers other proteins, like TBK1 and IRF3, to activate. These proteins then enter the nucleus, turning on genes that lead to an immune response, producing molecules like interleukin 2 (IL-2) and IL-6 to fight off infections or tumors. IKK, inhibitor of kappaB kinase; cGAMP, cyclic GMP-AMP; GTP, guanosine triphosphate; ATP, adenosine triphosphate; IκBα, inhibitory subunit of NF kappa B alpha; NF-κB, nuclear factor kappa-B; ISGs, interferon-stimulated genes.

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  2.2 Potential of STING agonists in cancer therapy

  Several types of STING agonists have been identified and are primarily categorized into three groups: cyclic dinucleotides (CDNs) and their derivatives, 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and its analogs, and small-molecule agonists [18]. Synthetic CDNs, such as ADU-S100 and MK-1454, along with non-nucleotide STING agonists, including diABZI, SR-717, and MSA-2, have been developed to address the metabolic instability of natural CDNs (Table 1 [27–32]). These synthetic molecules exhibit improved stability, enhanced anti-tumor efficacy, and versatile delivery approaches, making them valuable tools in cancer immunotherapy. Furthermore, the combination of STING agonists with ICIs or CAR-T cell therapy has demonstrated significant potential in strengthening anti-tumor immune responses. By activating innate immunity (Fig. S1 in Supporting information), reprogramming the TME, and promoting adaptive immune activation, STING agonists synergize with these therapies to enhance therapeutic efficacy, offering promising advancements for the treatment of solid tumors. Details on STING agonists and their combination with other immunotherapies can be found in Supporting information 1.2 [33–38].

  Table 1

  

  Table 1.  Overview of STING agonists, their example drugs, and mechanism descriptions.

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  Category	Example drugs	Description	Ref.
  Synthetic CDNs	ADU-S100	First STING agonist in human clinical trials. Showed good tolerability in advanced tumors	[27]
  	IACS-8779, IACS-8803	Potent CDN STING agonists with targeted modifications. Demonstrated superior anti-tumor responses in melanoma models	[28]
  	MK-1454	Synthetic CDN analog for advanced/metastatic solid tumors or lymphomas. Showed good activity and safety in phase Ⅰ trials	[27]
  DMXAA and analogs	DMXAA (ASA404, Vadimezan)	Induces apoptosis in tumor endothelial cells, disrupts tumor vascular system, and activates innate immune system	[29]
  Small molecule agonists	diABZI	First effective non-nucleotide STING agonist. Enhances binding affinity and induces CD8+ T cell responses	[30]
  	SR-717	Orally available non-nucleotide STING agonist with concomitant induction of PD-L1 expression	[31]
  	MSA-2	Orally available, weakly acidic, non-nucleotide STING agonist that activates as homodimers	[32]

  2.3 Challenges in STING activation therapy and cholesterol regulation as a potential solution

  Although the STING pathway plays a pivotal role in immune modulation, several challenges remain in optimizing its application in cancer immunotherapy. STING agonists have demonstrated remarkable anti-tumor potential. However, excessive activation of STING can lead to continuous production of cytokines, resulting in uncontrolled inflammation and cytokine storms, tissue toxicity, autoimmunity, and an inflammatory tumor microenvironment that promotes tumor growth. Therefore, it is necessary to precisely control the dosage of STING agonists to maximize therapeutic efficacy while minimizing immunotoxicity. Since STING is widely expressed in both immune and non-immune cells, systemic administration of STING agonists can also induce normal tissues to produce inflammatory cytokines. Consequently, current STING agonists in clinical trials are administered via intratumoral injection, which limits their application [33,39–42]. This dual role complicates the clinical use of STING agonists. Prolonged activation in tumors may bypass cell-cycle control mechanisms, enabling inflammatory processes that inadvertently support tumor growth. Early phase Ⅰ clinical trials combining STING agonists, like ADU-S100 and MK-1454, with ICIs have shown limited efficacy [43]. This raises questions regarding the suitability of STING as a clinical target. Some researchers attribute the lack of effectiveness to insufficient tumor doses or the high activation threshold of STING. Lowering the activation threshold of STING could offer an additional strategy to strengthen its tumor-targeting capacity [44]. Recent studies have found that high cholesterol levels in tumor cells can inhibit STING activation. Cholesterol in the ER interacts with the STING protein, affecting its trafficking and activation. Tumor in tissues such as breast, ovarian, uterine, thyroid, and renal cancers often contain higher cholesterol levels than normal tissues, supporting rapid cancer cell proliferation. Consequently, lowering cholesterol in cancer cells has been proposed as a therapeutic means [45]. Cholesterol depletion, as shown in studies using methyl-β-cyclodextrin (MβCD), restricts tumor cell survival and aggressiveness, and enhances the STING-driven anti-tumor response alongside ICIs [44]. Cholesterol in the ER regulates the STING pathway by interacting with cholesterol recognition/interaction amino acid consensus (CRAC) motifs in the STING protein sequence. Reduced ER cholesterol levels, achieved with cholesterol-lowering agents, lower the activation threshold for STING trafficking, thereby promoting pathway activation. Therefore, modulating cellular cholesterol levels presents a promising strategy to enhance cancer immunotherapy through targeted STING activation.

  3. Association between cholesterol metabolism and STING activation in cancer therapy

  Cholesterol plays a crucial role in the growth and survival of mammalian cells, acting as a vital component of cellular membranes and serving as a precursor for bile acids and steroid hormones, which are implicated in the initiation and progression of cancers, including those of the colon, breast, and prostate. Moreover, cholesterol modulates signaling pathways related to tumorigenesis by covalently modifying proteins such as hedgehog and smoothened and supporting the formation of specialized membrane microdomains. Cancer cells, which proliferate rapidly, have an increased demand for cholesterol to support membrane biogenesis and other essential processes. For example, the cholesterol-derived oncometabolite 6-oxo-cholestan-3β, 5α-diol, found at elevated levels in breast cancer patients, binds to glucocorticoid receptors to promote tumor growth. Thus, cholesterol metabolism plays a pivotal role in driving cancer progression by enhancing cell proliferation, migration, and invasion [46]. Consequently, strategies that deplete cholesterol or disrupt its trafficking have been shown to effectively suppress tumor growth and invasion across various cancer types. Cholesterol homeostasis is regulated through four key processes: biosynthesis, uptake, esterification, and export. These processes involve coordinated actions of enzymes, transporters, and transcription factors like sterol regulatory element-binding protein 2 (SREBP2) and liver X receptors (LXRs), which regulate cholesterol levels, storage, and efflux in response to cellular needs. Furthermore, cholesterol and its metabolites, including intermediates and derivatives, influence tumor progression and immune cell functions within the tumor microenvironment, promoting tumor growth by enhancing cholesterol uptake by tumor cells, reprogramming macrophages into an immunosuppressive phenotype, and modulating dendritic cell antigen presentation. As a result, cholesterol metabolism emerges as a critical target for advancing cancer immunotherapy. For details, please refer to Supporting information 2.1 [47–55], 2.2 [56–60], and Fig. S2 (Supporting information).

  3.1 Role of cholesterol and lipid rafts in immune signaling

  Cholesterol influences cell membrane properties, including fluidity and negative membrane curvature [18,61]. Cholesterol-rich lipid rafts are essential for TLR signaling, a critical component of the innate immune system responsible for pathogen detection. Lipid rafts are critical for the localization and activation of TLR family members, which include 10 receptors, some on the cell surface (TLR1, TLR2, TLR4, TLR5, TLR6) and others intracellularly (TLR3, TLR7, TLR8, TLR9). TLRs detect pathogen-associated molecular patterns, inducing the release of pro-inflammatory cytokines [62]. For example, the immune response to bacterial lipopolysaccharide (LPS) begins when LPS binds to lipopolysaccharide-binding protein (LBP), which then associates with cluster of differentiation 14 (CD14), a glycoprotein in lipid rafts. CD14 conveys signals by interacting with TLR4 and recruiting downstream signaling molecules [62]. Microscopy techniques, such as Förster resonance energy transfer (FRET) and fluorescence recovery after photobleaching (FRAP), show that LPS induces TLR4 clustering within lipid rafts. Other raft-associated proteins, such as CD36, CD44, and heat shock protein 90 (HSP9), also participate in TLR4 signaling and recognize both microbial and non-microbial ligands [63]. Multiple TLRs contain CRAC sequences within their intracellular juxtamembrane domains, suggesting that cholesterol may directly impact TLR activation. Polyunsaturated fatty acids inhibit TLR signaling by blocking receptor dimerization and recruitment to lipid rafts [62]. Elevated cellular cholesterol promotes additional lipid raft formation, amplifying TLR signaling. Cholesterol-loading through a cyclodextrin–cholesterol complex activates TLR4 signaling in the plasma membrane and TLR3 signaling in the endosomal membrane of macrophages [64]. Similarly, lipid rafts regulate the STING pathway, essential for the innate immune response to cytosolic DNA from pathogens or damaged cells. Like TLRs, STING pathway function relies on localization within lipid rafts. Cholesterol in these microdomains contributes to membrane organization, fluidity, and curvature, which are critical for STING activation and trafficking. Under normal conditions, STING is localized in the ER, upon activation by cGAS, it translocates to the Golgi apparatus, initiating immune signaling. Cholesterol in lipid rafts facilitates this translocation process by supporting the membrane dynamics essential for STING trafficking.

  3.2 Cholesterol regulation of the STING pathway in cancer therapy

  Recent studies reveal that cholesterol levels play a critical role in regulating STING activation. Cholesterol depletion, achieved through agents like MβCD, enhances STING signaling by promoting STING oligomerization—which is essential for its activation—without impacting dimerization. Furthermore, genetic disruptions of cholesterol-related genes, such as 2,3-oxidosqualene-lanosterol cyclase (LSS, involved in cholesterol biosynthesis) and ATP binding cassette transporter G1 (ABCG1, involved in cholesterol transport), further emphasize cholesterol's regulatory role. Specifically, LSS deficiency, which reduces cholesterol levels, increased phosphorylation of STING, tank-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3), while ABCG1 deficiency, resulting in cholesterol accumulation, reduced phosphorylation of these proteins. Notably, MβCD treatment restored phosphorylation levels in ABCG1-deficient cells, highlighting cholesterol's inhibitory effect on STING activation. Additionally, MβCD enhances STING's interactions with TBK1 and other proteins in the cGAMP pathway, directly impacting phosphorylation and protein interactions. Cholesterol also influences STING trafficking; its depletion facilitates STING mobilization from cholesterol-rich lipid rafts, allowing STING to move from the ER to the Golgi apparatus. Confocal microscopy showed that MβCD-treated cells exhibited reduced colocalization of STING with the ER marker PDI and increased colocalization with the Golgi marker GM130, suggesting enhanced trafficking (Fig. 2) [65–67]. In vitro assays confirmed these findings, demonstrating that cholesterol depletion increased Sec24 foci and coat protein II (COPII) complex formation, which are essential for vesicular transport [65,66]. Conversely, cholesterol addition reversed these effects, underscoring its regulatory role in STING activation and trafficking.

  Figure 2

  

  Figure 2.  Interaction between cholesterol metabolism and the STING pathway. Cholesterol is transported from the lysosome by NPC1, influencing STING activation in the ER. STING then translocates to the Golgi, where it activates IRF3, leading to IFN production. Cholesterol regulates this process through molecules like SOAT1 and SCAP-SREBP2, which can either promote or inhibit STING activation and signaling. The diagram highlights cholesterol's role in regulating both metabolism and immune responses.

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  Excess membrane cholesterol inhibits STING activation by anchoring it within the ER and blocking its trafficking to the Golgi apparatus. Cholesterol binds to STING through two CRAC motifs located in the TM2–TM3 linker region and the connector loop to the ligand-binding domain [44,68]. This binding effectively restricts STING's exit from the ER, thus modulating its signaling pathway (Fig. 2) [67]. This mechanism, often exploited in TMEs, suppresses immune activation and allows cancer cells to evade immune detection. Studies disrupting these CRAC motifs in STING showed reduced cholesterol binding, confirming cholesterol's role in controlling STING activation. Cholesterol pull-down and mass spectrometry experiments further supported this finding by revealing decreased cholesterol association with mutant STING proteins. Interestingly, early cGAMP stimulation temporarily reduces cholesterol levels in the ER. This reduction is facilitated by sterol O-acyltransferase 1 (SOAT1), which esterifies cholesterol, thereby altering ER membrane fluidity and enabling STING to be released [44]. The decrease in cholesterol promotes membrane curvature, allowing STING to exit the ER and proceed to the Golgi apparatus. As cGAMP stimulation progresses, cholesterol levels in the ER recover, acting as a "brake" to reset STING activation and maintain cellular homeostasis. Thus, cholesterol plays a dual regulatory role in STING activation: it enhances activation through depletion and inhibits it when in excess, offering potential therapeutic strategies for immune modulation.

  Targeting cholesterol metabolism to modulate STING activation holds promise for enhancing anti-tumor immunity, especially in combination with STING agonists and other immunotherapies. Recent findings highlight the role of Niemann-Pick type C1 (NPC1), a lysosomal membrane protein crucial for cholesterol transport, in STING regulation [66]. NPC1 knockout impairs cholesterol transport, leading to its accumulation in lysosomes and blocking its transfer to the ER. This disruption strengthens STING signaling by facilitating STING's interaction with the SREBP cleavage activating protein (SCAP)–sterol regulatory element binding protein-2 (SREBP2) complex, enhancing its transport from the ER to the Golgi apparatus for activation. Consequently, the loss of NPC1 leads to sustained STING activation and chronic inflammation, underscoring cholesterol's role in controlling STING trafficking and maintaining cellular homeostasis [65,67]. Furthermore, lipid metabolism is intricately linked to immune regulation through shared precursors and pathways. Acetyl-CoA, a precursor for both cholesterol and polyunsaturated fatty acids (PUFAs), connects cholesterol metabolism to PUFA synthesis [69]. While cholesterol synthesis follows the mevalonate pathway, PUFAs are produced through fatty acid elongation and desaturation and serve as transcription factor activators that influence glucose and lipid metabolism. STING regulates metabolic homeostasis by interacting with fatty acid desaturase 2 (FADS2), which is essential for PUFA synthesis [70]. Upon STING activation, its interaction with FADS2 diminishes, leading to increased FADS2 activity, PUFA desaturation, and subsequent metabolic changes. PUFAs and their derivatives, produced by FADS2 activity, can inhibit STING, thereby regulating IFN-I responses and alleviating inflammation. Moreover, PUFAs aid cholesterol removal by upregulating ATP-binding cassette transporter A1 (ABCA1), which transports cholesterol to high-density lipoprotein (HDL) for excretion, maintaining cellular cholesterol balance. Low cholesterol levels enhance STING trafficking from the ER to the Golgi, boosting activation of STING-mediated immune responses against tumors, whereas high cholesterol levels inhibit this process (Fig. 2 and Fig. S3 in Supporting information).

  These findings suggest that modulating cholesterol metabolism could provide a therapeutic strategy to influence STING activation and improve cancer immunotherapy outcomes [71]. Unlike STING agonists such as 2′,3′-cGAMP, which activate STING by directly binding to its cytosolic domain and facilitating its translocation to the Golgi apparatus to activate downstream targets, cholesterol-lowering agents activate the STING pathway indirectly by altering intracellular cholesterol levels. A reduction in cholesterol within the ER promotes the trafficking of STING to the Golgi apparatus, thereby enhancing its activation. This process effectively lowers the threshold required for STING activation, facilitating a controlled and efficient immune response. By activating STING indirectly, these agents mitigate the risk of overstimulation, which can lead to chronic inflammation and immune-related toxicity—common concerns associated with direct STING agonists. The clinical applicability of high-dose cholesterol-lowering therapies is limited by several factors that underscore the need for careful consideration in their use. Despite their efficacy in achieving substantial reductions in cholesterol, high-dose lipid-lowering strategies often pose challenges related to tolerability, patient adherence, and long-term safety. Adverse effects, although variable in severity, can impact patients' willingness to maintain therapy and influence the overall success of treatment outcomes [72]. Therefore, repurposing approved cholesterol-regulating drugs via NPs mediation may be a more effective way to elicit STING activation compared to traditional STING agonists (Fig. 3).

  Figure 3

  

  Figure 3.  The figure illustrates the relationship between the activation level of the STING pathway and different therapeutic strategies. The vertical axis represents the level of STING activation, ranging from insufficient activation to proper activation and over-activation. The horizontal axis represents the intervention strategies.

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  4. Designing nanomedicines at the interface of lipid metabolism and innate immunity

  Targeting innate immunity provides a potent therapeutic approach to enhance the efficacy of cancer treatment. In this context, NPs ranging from 10 nm to 400 nm in diameter present an advanced platform for cancer therapy by being functionalized with targeting ligands or encapsulating therapeutic agents. The primary benefits of using NPs in cancer treatment include their small size, which enables efficient absorption and diffusion; their capacity to carry multiple targeting and therapeutic agents; their ability to overcome biological barriers; and their facilitation of sustained or stimulus-triggered drug release [18,73,74]. Consequently, researchers are actively designing NPs to enhance cancer treatment outcomes by targeting components of TME and reversing its immunosuppressive activity [18,75]. Many nanomaterials—such as lipid nanoparticles (LNPs), extracellular vesicles, inorganic NPs, and polymeric NPs—have been developed to deliver small nucleic acids, proteins, and molecules [18,76]. Each type of NP offers distinct advantages: lipid-based NPs are easy to formulate and exhibit high bioavailability; polymeric NPs provide payload flexibility and ease of surface modification; inorganic NPs exhibit distinctive physical properties (optical, magnetic, and electrical) and tunable sizes; and extracellular vesicles share the membrane topology of their origin cells and exhibit lower immunogenicity [18,77,78]. By combining these NP-specific properties with their broader advantages as delivery systems, researchers can tackle the limitations of traditional immune cell-modulating therapies [18]. NPs can transport antigens to immune cells either by co-delivering with the antigens or by protecting and releasing them at target sites. Additionally, as adjuvants, NPs can enhance immune responses by activating immune pathways, boosting antigen processing, and improving immunogenicity. In the following sections, we will discuss in depth the NPs materials, fabricating polymers, surface charge and size, and payloads, aiming to provide novel insights into cholesterol metabolism regulation associated with STING activation.

  NPs, regardless of the drugs they carry, are foreign to the human body, much like dust and other impurities. As a result, most NPs do not provoke a strong innate immune response and are quickly cleared from the system. However, in certain cases, innate immunity can be activated. This occurs due to a series of changes that NPs undergo upon entering the body, including physical aggregation and the adsorption of a protein corona, which increases their size. The enlarged particles are more readily recognized and taken up by macrophages, thus triggering an innate immune response. The ability of NPs to induce innate immunity is influenced by factors such as material composition, size, and surface charge (Fig. 4a). However, this immune activation is generally uncontrollable, and its intensity is often insufficient to serve as a therapeutic strategy. Different types of NPs, including those composed of lipids, polysaccharides, metals, and synthetic polymers, along with their size, shape, and charge, can significantly impact innate immunity and the tumor microenvironment. By adjusting their composition and payloads, such as incorporating statins, NPs can reprogram immune cells like macrophages, dendritic cells, and natural killer cells (NKs), thereby enhancing anti-tumor responses and potentially improving the efficacy of immunotherapies. For details, please refer to Supporting information 3.1 [79–85], 3.2 [86–88], 3.3 [89–92].

  Figure 4

  

  Figure 4.  The image illustrates how nanomaterials can be used to enhance drug delivery, specifically targeting cholesterol reduction and promoting STING pathway activation for innate immune responses. (a) Different nanomaterials (polysaccharides, lipids, polymers, metals, and nucleic acids) can be tailored by shape, size, and charge to optimize delivery. (b) Strategy for statins as hydrophobic fragments for amphiphilic polymer preparation and self-assembly into NPs. (c) Strategy for statins as hydrophobic drugs encapsulated inside NPs. (d) Various nanomaterial shapes (sphere, rod, sheet) can improve mucus infiltration and receptor activation, further enhancing the drug's efficacy.

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  Lipid-lowering drugs are primarily hydrophobic, and three primary nanoparticle delivery systems—liposomes, poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles, and LNPs—have been extensively investigated. Liposomes are vesicular structures formed by phospholipid bilayers, within which hydrophobic drugs are embedded [93]. This embedding enhances the solubility and stability of the drugs. However, a high drug loading may compromise the stability of the bilayer and impact membrane fluidity. PLGA nanoparticles, typically solid or semi-solid spheres, allow hydrophobic drugs to be dissolved or dispersed within the PLGA matrix. Due to PLGA's hydrophobic nature, it facilitates high encapsulation efficiency, which can be further enhanced by modifying parameters such as molecular weight, solvent system, and drug loading method. As PLGA degrades, drug release occurs gradually, making it suitable for sustained, controlled release applications [94]. LNPs consist of a solid or semi-solid lipid core surrounded by a monolayer shell of phospholipids or surfactants, in which hydrophobic drugs are housed, effectively isolating them from the external aqueous environment. Like solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), LNPs exhibit high encapsulation efficiency. Their release rates are influenced by the lipid composition, membrane permeability, and fluidity, which can be regulated by modifying phospholipid types, cholesterol ratios, and PEGylation. In vivo, LNPs can gradually release drugs through interactions with plasma proteins, enzymatic degradation, and apolipoproteins, thus targeting specific tissues for sustained drug delivery [95,96].

  4.1 Various lipid-lowering drugs suitable as NPs payloads to activate STING

  (1) Statins

  Statins are widely prescribed as the primary pharmacological treatment for reducing cardiovascular risk by inhibiting cholesterol synthesis [97,98]. The primary mechanism of action involves the competitive inhibition of 3–hydroxy-3-methylglutaryl-CoA reductase (HMGCR), which is the rate-limiting enzyme responsible for the conversion of HMG-CoA to mevalonic acid, a crucial intermediate in the biosynthesis of cholesterol [99]. By blocking this step, statins effectively lower cholesterol production in the liver. Beyond reducing cholesterol biosynthesis, statins also activate anti-tumor immune responses by reprogramming TAMs and enhancing the function of NKs. Cholesterol depletion—achieved through treatments with agents like MβCD—can remove cholesterol from the ER, altering ER morphology and promoting the delivery of STING from the ER to the Golgi apparatus. This relocation is essential for initiating STING signaling, as STING must exit the ER and move to other organelles to activate downstream immune pathways. Moreover, restoring cholesterol levels can reset STING activation, preventing excessive or chronic signaling and restoring cellular homeostasis [44]. Thus, statins may serve as a vital player in modulating STING activation, offering potential therapeutic benefits in conditions involving overactive STING signaling. Given the low bioavailability, low water solubility, rapid metabolism, and various clinical complications associated with statins, it is beneficial to improve their therapeutic efficacy and minimize side effects by exploring alternative therapeutic strategies, including nanomedicine-based approaches [100,101].

  Chitosan, a biopolymer used for coating liposomes to improve stability and facilitate controlled drug release, has been shown to enhance the efficiency of nanoformulations and increase drug accessibility. Moreover, chitosan itself has been reported to reduce cholesterol levels, as validated in both human and animal studies [102]. Atorvastatin calcium-loaded chitosan NPs have demonstrated the capability for sustained drug release lasting up to seven days [103]. These NPs are effective in delivering statins to immune cells, including macrophages and dendritic cells (DCs), thereby modulating the activation of the STING pathway. By precisely modulating STING pathway activation, chitosan NPs help prevent chronic inflammatory responses caused by STING overactivation, thereby achieving immune homeostasis [90]. Among lipid-based NPs formulations, SLNs and NLCs are well-studied delivery systems [104]. Compared to free statins, SLN-loaded statins show significantly enhanced oral bioavailability and absorption [105,106]. LNPs can accurately deliver statins to immune cells, and modulate the STING pathway, reducing chronic inflammation caused by STING overactivation and maintaining immune balance. Through STING pathway regulation, statin-loaded LNPs are effective in preventing the development of autoimmune diseases [90]. Biodegradable polymer NPs, such as PLGA, have also been thoroughly investigated in conjunction with statins. PLGA, a Food and Drug Administration (FDA)-approved polymer, enhances bioavailability, controls drug release, minimizes adverse effects, and reduces dosing frequency [107]. For instance, in a hyperlipidemic rat model system, atorvastatin-loaded PLGA NPs administered every three days achieved comparable efficacy to daily treatment with the commercial formulation Lipicure, resulting in a 66% reduction in the required daily dose of atorvastatin. Additionally, statin-loaded PLGA NPs have been shown to slow hypertension progression and inhibit pulmonary smooth muscle cell proliferation, offering cardioprotective benefits without adverse effects. More recently, cellulose-based polymer NPs have demonstrated a 3.5-fold increase in drug bioavailability, with atorvastatin-loaded ethyl cellulose NPs showing promise for future clinical trials [101,108]. Statins modulate the STING signaling pathway via polymer NPs, avoiding chronic inflammation caused by overactivation and helping maintain immune balance.

  (2) Ezetimibe

  Ezetimibe reduces blood cholesterol levels by inhibiting cholesterol absorption in the small intestine. The molecular target of ezetimibe is the sterol carrier NPC 1L1, which is implicated in the intestinal absorption of cholesterol and phytosterols. Ezetimibe attaches to the brush border of the small intestinal villous epithelium and inhibits cholesterol absorption, thereby decreasing the transport of cholesterol from the small intestine to the liver, resulting in a decrease in hepatic cholesterol stores and an increase in blood cholesterol clearance [98]. Furthermore, the cholesterol metabolism pathway regulated by NPC 1L1 has been found to potentially exert an inhibitory regulatory effect on the STING signaling pathway. Studies have indicated that excessively high intracellular cholesterol levels inhibit STING activation. By regulating cholesterol metabolism, NPC 1L1 may help maintain the proper function of the STING pathway, preventing disruptions in signal transmission caused by cholesterol overload. Lipid carrier systems, such as SLNs, have been proven to effectively increase the bioavailability of ezetimibe. Ezetimibe-loaded SLNs demonstrate superior stability compared to marketed products and drug suspensions, maintaining this stability for up to three months [18]. Beyond enhancing bioavailability, lipid-based carriers can help regulate cholesterol metabolism, supporting normal function of the STING pathway and preventing signal transmission issues due to cholesterol accumulation. By modulating the STING pathway, ezetimibe-loaded lipid carriers can reduce chronic inflammatory responses and mitigate immune disorders linked to abnormal cholesterol metabolism. Moreover, these lipid carriers can diminish the immunosuppressive effects of ezetimibe while maintaining proper immune system function.

  (3) Acetyl-coenzyme A acetyltransferase 1 (ACAT1) inhibitors

  ACAT1 is an enzyme situated in the ER membrane, primarily responsible for converting free cholesterol into cholesterol esters for storage, thus maintaining intracellular cholesterol homeostasis. Studies have indicated that reducing cholesterol esterification in T cells can significantly enhance their function within the TME, increasing their capacity to destroy tumor cells. The activation of STING, a key player in the immune response, depends on a specific cholesterol microenvironment; excessive cholesterol inhibits STING transport, while lower cholesterol levels facilitate STING activation. ACAT1 serves a vital role in cholesterol metabolism and lipid storage and is implicated in disease states such as atherosclerosis, neurodegenerative diseases, and cancer. By inhibiting cholesterol ester formation, ACAT1 inhibitors help regulate intracellular cholesterol levels. Several ACAT1 inhibitors have shown potential in research, including Avasimibe and K-604. Avasimibe was used in clinical trials primarily for treating atherosclerosis but was not successfully marketed due to concerns over side effects and efficacy. K-604, recognized as a more selective inhibitor of ACAT1, has shown significant anti-atherosclerotic effects in initial investigations. Consequently, further extensive research is required to examine the potential of ACAT1 inhibitors as modulators of STING [109].

  Different lipid-lowering drugs operate via distinct mechanisms to lower cholesterol levels, which then exerts an impact on innate immunity through the signaling regulation of the cholesterol-STING pathway. In an effort to heighten the effect of lipid-lowering drugs in this respect and to realize further anti-tumor efficacy, intelligent nano-delivery systems can be employed to offer nanoscale effects and more potent immune-inducing capabilities within the TME.

  4.2 Nanoparticulation's STING augmenting effects for lipid-lowering drugs

  Lipid-lowering drugs reduce intracellular cholesterol levels by different mechanisms. As previously noted, an inverse relationship exists between cholesterol levels and the activation of the cGAS-STING pathway. Therefore, delivering cholesterol-lowering drugs in the form of NPs to the target site may enhance innate immune activation. Taking statins—a representative class of cholesterol-lowering drugs—as an example, there are generally three NP-based delivery strategies: (1) Encapsulating statins in the core of NPs; (2) covalently linking statins to nanomaterial shells; and (3) designing statins as nanocrystals to improve their physical properties. Each of these strategies offers unique advantages and limitations. The first strategy is a traditional drug delivery approach, where the statin is encapsulated within the NP core and released after cellular uptake. For instance, in one study, simvastatin was encapsulated within cyclodextrin-based NPs. Upon reaching areas of high cholesterol expression, the cyclodextrins—having a higher affinity for cholesterol than simvastatin—effectively exchanged simvastatin for cholesterol, thereby removing cholesterol and releasing the statin [110]. The second strategy involves covalently linking statins to nanomaterials through chemical reactions, which requires careful design but offers advantages in precise drug release. The linkage can be engineered to be responsive, breaking to release the drug in response to specific characteristics of target cells, such as macrophages or cancer cells. Moreover, statin-modified shells can be utilized for the co-delivery of additional drugs. For example, hydrophobic atorvastatin was coupled with galactose-modified trimethyl chitosan to form NPs capable of loading siRNA and pDNA, thereby reducing cholesterol synthesis and improving drug bioavailability [111]. The third strategy uses excipient-free nanocrystals to enhance drug bioavailability. Statins, being hydrophobic, benefit from nanocrystal technology to improve solubility in oral or injectable formulations. Nanocrystals increase surface area by reducing particle size, which enhances drug uptake and receptor agonism. One study found that rod-shaped statin nanocrystals exhibited better mucus permeability, trans-epithelial transport, and higher plasma exposure compared to other shapes (Figs. 4b–d) [112].

  In addition to the improvement in statin delivery by NPs, the materials required for the composition of the NPs themselves may also provide assistance to statins in improving STING pathway activation. As mentioned earlier, various nanomaterials including lipids, polysaccharides, metals, etc., have the ability to activate innate immunity on their own. Artificially designed and synthesized lipid materials have TLR activation properties, and such adjuvant lipids can be used as synthetic materials for LNP or liposomes, and the nanocarriers constructed for the delivery of statins can achieve dual activation of innate immunity. Among polysaccharide materials, chitosan is the most commonly used in conjunction with statins, and several delivery systems have been used to deliver statins via chitosan for anti-atherosclerotic therapy, but no studies have been conducted on STING pathway activation for anti-tumor therapy. Chitosan itself, as previously reported, has the property of activating NKs, DCs, and can participate in innate immunity in response to the IFN pathway, which, in combination with the cholesterol-lowering effect of statins, could result in good innate immunity maximization. Cyclodextrins are also a form of polysaccharide, and hydroxypropyl-β-cyclodextrin (HPCD) has shown the ability to solubilize cholesterol and can be engineered into nanopremedies to improve drug efficacy [113], which can be further amplified when used in combination with statins to lower cholesterol. Metallic materials that are more relevant to statins are zinc ions and iron ions. Zinc ions can significantly enhance the STING pathway signaling and facilitate the infiltration of CD8⁺ T cells into tumor tissues [114], which is complementary to the STING pathway-inducing properties of statins. Iron ions can promote the peroxidation of PUFA and further reduce the inhibition of STING protein by PUFA, and the peroxidised PUFA can lead to mitochondrial oxidative stress, which can activate the STING pathway, whereas statins can avoid the interference of the intracellular cholesterol level on the subsequent activation of STING, and achieve a heightened activation of the STING pathway [115]. miRNAs are common non-coding RNAs used to target and regulate mRNAs, which in turn perform a variety of biological functions, including regulation of lipid metabolism and promotion of apoptosis in cancer cells. Exosomes serve as outstanding delivery vehicles for nucleic acid drugs, possessing numerous advantages like traversing biological barriers and attaining long-distance communication among cells [116]. HDLs have the potential to serve as drug delivery carriers, and a growing number of studies are utilizing them to target tumor tissues. Furthermore, HDLs serves both as a regulator of cholesterol metabolism and as a scavenger of oxidized low-density lipoproteins (LDLs), thereby it may be ideally suitable for being used in anti-tumor cholesterol-modulating therapies [117].

  To more effectively improve the function of NPs in cholesterol homeostasis and thereby the stimulation of the STING pathway, NPs can be further engineered (Fig. S4 in Supporting information). This includes the following four aspects: (1) Surface modification of NPs, for example with long-cycle polymers, engineered proteins, antibodies, and targeting ligands, which subsequently provides a range of functionalities, such as tumor targeting, cell adhesion, and immune checkpoint-blocking therapeutic conjugation. (2) The selection of carrier substances, which has been previously examined and primarily includes polysaccharides, lipids, polymeric materials, metallic materials, and biomimetic carriers. (3) The controlled release of NPs. The TME presents distinct biochemical indicators relative to normal tissues, which can therefore be utilized to create responsive release carriers for drugs to prevent the premature release of agents, such as being reactive oxygen species (ROS)-sensitive, glutathione (GSH)-sensitive, low pH-sensitive, hypoxia-sensitive, and simultaneously, it can be integrated with photothermal therapy to obtain temperature sensitivity after gradually increasing the temperature of local tumor tissues. (4) The co-administration of multiple agents. In addition to cholesterol-regulating agents, NPs can be simultaneously loaded with photosensitizers, peptides, nano-enzymes, chemotherapy agents, nucleic acid therapeutics, etc., which in turn can induce STING activation in combination with multiple therapies to enhance anti-tumor efficacy. For example, LNPs are used to deliver mRNAs used to regulate lipid metabolism to organs at different tumor lesion sites for targeted therapeutic effects [118]. In summary, NPs formulated from various materials assume distinct roles in delivering cholesterol-lowering agents. Combining NPs with statins can improve statin utilization, maintaining their cholesterol-lowering effects and STING pathway activation. Additionally, NP dimensions and composition selection can further amplify STING pathway activation by statins, boosting immune function through intrinsic immune cells.

  5. Discussion and outlook

  Cholesterol metabolism serves as a critical regulator of the STING pathway, presenting a novel strategy to enhance innate immune responses in cancer treatment. Lipid-lowering agents such as statins, by reducing intracellular cholesterol levels, have shown the potential to enhance STING activation, thereby overcoming tumor-mediated immune evasion and strengthening anti-tumor immunity. When integrated with nanotechnology, these agents offer transformative possibilities, enabling precise drug delivery, improved bioavailability, and reduced off-target effects. NPs that simultaneously deliver STING agonists and cholesterol-lowering drugs hold significant promise for fine-tuning immune responses while mitigating the risks associated with chronic inflammation. Advancing the design of NPs to specifically target cholesterol metabolism within the TME is a critical focus for future research. Such advancements could meaningfully improve immunotherapy by addressing persistent challenges, including immune resistance and the immunosuppressive nature of the TME. Additionally, deeper investigations into the connections between cholesterol metabolism and immune pathways have the potential to inspire innovation in multiple areas, such as combination therapies involving ICIs, CAR-T cell therapies, and personalized cancer vaccines.

  Outside the field of oncology, the regulation of cholesterol metabolism using nanomedicine may have applications in the treatment of autoimmune diseases, infectious diseases, and metabolic disorders. Realizing the full potential of this approach will require a multidisciplinary research framework encompassing molecular biology, immunology, and nanotechnology. Ultimately, this paradigm has the capacity to revolutionize cancer therapy and extend its influence across various medical disciplines, paving the way for more effective and individualized therapeutic strategies.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Chengying Wang: Writing – original draft, Visualization. Bohan Chen: Writing – original draft, Visualization. Yuming Wang: Writing – original draft, Formal analysis. Bingyu Xie: Investigation. Peishuang Yu: Investigation. Xiaojie Xu: Investigation. Rui Wang: Formal analysis. Lin Miao: Investigation. Xiaohui Yan: Investigation. Yubo Li: Supervision. Yunfei Li: Writing – review & editing, Funding acquisition, Conceptualization. Wei Huang: Writing – review & editing, Funding acquisition.

  Acknowledgments

  This work was funded by Open Projects Fund of Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University (No. 2023CCG13, China), Tianjin University of Traditional Chinese Medicine Startup Funding to Yunfei Li, and CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1–026, China), and National Key R & D Program of China (No. 2019YFA090530).

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2025.110921.

  
  
• 1. [1]

     X. Dong, S. Xia, S. Du, et al., ACS Cent. Sci. 9 (2023) 1864–1893. doi: 10.1021/acscentsci.3c00702

  2. [2]

     J.L. Adams, J. Smothers, R. Srinivasan, A. Hoos, Nat. Rev. Drug Discov. 14 (2015) 603–622. doi: 10.1038/nrd4596

  3. [3]

     M.D. Vesely, M.H. Kershaw, R.D. Schreiber, M.J. Smyth, Annu. Rev. Immunol. 29 (2011) 235–271. doi: 10.1146/annurev-immunol-031210-101324

  4. [4]

     R.D. Schreiber, L.J. Old, M.J. Smyth, Science 331 (2011) 1565–1570. doi: 10.1126/science.1203486

  5. [5]

     I. Mellman, G. Coukos, G. Dranoff, Nature 480 (2011) 480–489. doi: 10.1038/nature10673

  6. [6]

     T.A. Gardner, B.D. Elzey, N.M. Hahn, Hum. Vaccin. Immunother. 8 (2012) 534–539. doi: 10.4161/hv.19795

  7. [7]

     P.C. Buchsel, A. Forgey, F.B. Grape, S.S. Hamann, Clin. J. Oncol. Nurs. 6 (2002) 198–205. doi: 10.1188/02.CJON.198-205

  8. [8]

     J. Raja, J.M. Ludwig, S.N. Gettinger, et al., J. Immunother. Cancer 6 (2018) 140. doi: 10.1186/s40425-018-0458-z

  9. [9]

     M. Aris, M.M. Barrio, Front. Immunol. 6 (2015) 46.

  10. [10]

      B.M. Barton, R. Xu, E.J. Wherry, P.M. Porrett, J. Leukoc. Biol. 101 (2017) 975–987. doi: 10.1189/jlb.1A0316-135R

  11. [11]

      Y.J. Shim, R. Khedraki, J. Dhar, et al., Kidney Int. 98 (2020) 897–905. doi: 10.1016/j.kint.2020.03.037

  12. [12]

      P. Sharma, J.P. Allison, Science 348 (2015) 56–61. doi: 10.1126/science.aaa8172

  13. [13]

      S.L. Topalian, J.M. Taube, R.A. Anders, D.M. Pardoll, Nat. Rev. Cancer 16 (2016) 275–287. doi: 10.1038/nrc.2016.36

  14. [14]

      M.A. Postow, R. Sidlow, M.D. Hellmann, N. Engl. J. Med. 378 (2018) 158–168. doi: 10.1056/NEJMra1703481

  15. [15]

      L. Corrales, T.F. Gajewski, Cytokine 77 (2016) 245–247. doi: 10.1016/j.cyto.2015.08.258

  16. [16]

      S.R. Woo, M.B. Fuertes, L. Corrales, et al., Immunity 41 (2014) 830–842. doi: 10.1016/j.immuni.2014.10.017

  17. [17]

      O. Demaria, A. De Gassart, S. Coso, et al., Proc. Natl. Acad. Sci. U. S. A. 112 (2015) 15408–15413. doi: 10.1073/pnas.1512832112

  18. [18]

      Y. Gan, X. Li, S. Han, et al., Front. Immunol. 12 (2021) 795401.

  19. [19]

      L.J. Sun, J.X. Wu, F.H. Du, et al., Science 339 (2013) 786–791. doi: 10.1126/science.1232458

  20. [20]

      S. Srikanth, J.S. Woo, B.B. Wu, et al., Nat. Immunol. 20 (2019) 152. doi: 10.1038/s41590-018-0287-8

  21. [21]

      K. Mukai, H. Konno, T. Akiba, et al., Nat. Commun. 7 (2016) 11932. doi: 10.1038/ncomms11932

  22. [22]

      H. Ishikawa, G.N. Barber, Nature 455 (2008) 674. doi: 10.1038/nature07317

  23. [23]

      T. Agalioti, S. Lomvardas, B. Parekh, et al., Cell 103 (2000) 667–678. doi: 10.1016/S0092-8674(00)00169-0

  24. [24]

      S. Grabosch, M. Bulatovic, F. Zeng, et al., Oncogene 38 (2019) 2380–2393. doi: 10.1038/s41388-018-0581-9

  25. [25]

      S.M. Harding, J.L. Benci, J. Irianto, et al., Nature 548 (2017) 466–470. doi: 10.1038/nature23470

  26. [26]

      C.Y. Ok, K.H. Young, J. Hematol. Oncol. 10 (2017) 103. doi: 10.1186/s13045-017-0474-3

  27. [27]

      S. Berry, N. Giraldo, P. Nguyen, et al., J. Immunother. Cancer 7 (2019) 46. doi: 10.1186/s40425-019-0519-y

  28. [28]

      C.R. Ager, H. Zhang, Z. Wei, et al., Bioorg. Med. Chem. Lett. 29 (2019) 126640. doi: 10.1016/j.bmcl.2019.126640

  29. [29]

      A. Daei Farshchi Adli, R. Jahanban-Esfahlan, K. Seidi, et al., Chem. Biol. Drug Des. 91 (2018) 996–1006. doi: 10.1111/cbdd.13166

  30. [30]

      L. Chen, S. Zhao, Y. Zhu, et al., Interdiscip. Sci. 13 (2021) 751–765. doi: 10.1007/s12539-021-00446-3

  31. [31]

      E.N. Chin, C. Yu, V.F. Vartabedian, et al., Science 369 (2020) 993–999. doi: 10.1126/science.abb4255

  32. [32]

      B. -S. Pan, S.A. Perera, J.A. Piesvaux, et al., Science 369 (2020) eaba6098. doi: 10.1126/science.aba6098

  33. [33]

      M. Jiang, P. Chen, L. Wang, et al., J. Hematol. Oncol. 13 (2020) 81. doi: 10.1186/s13045-020-00916-z

  34. [34]

      Y.S. Tan, K. Sansanaphongpricha, Y. Xie, et al., Clin. Cancer Res. 24 (2018) 4242–4255. doi: 10.1158/1078-0432.ccr-17-2807

  35. [35]

      Y. Pang, X. Hou, C. Yang, et al., Mol. Cancer 17 (2018) 91. doi: 10.1186/s12943-018-0840-y

  36. [36]

      K. Newick, S. O'Brien, E. Moon, S.M. Albelda, Annu. Rev. Med. 68 (2017) 139–152. doi: 10.1146/annurev-med-062315-120245

  37. [37]

      E. Zhang, J. Gu, H. Xu, Mol. Cancer 17 (2018) 7. doi: 10.1186/s12943-018-0759-3

  38. [38]

      T.T. Smith, H.F. Moffett, S.B. Stephan, et al., J. Clin. Invest. 127 (2017) 2176–2191. doi: 10.1172/JCI87624

  39. [39]

      Q. Chen, A. Boire, X. Jin, et al., Nature 533 (2016) 493–498. doi: 10.1038/nature18268

  40. [40]

      D. Liang, H. Xiao-Feng, D. Guan-Jun, et al., Biochim. Biophys. Acta 1852 (2015) 2494–2503. doi: 10.1016/j.bbadis.2015.08.011

  41. [41]

      H. Lemos, E. Mohamed, L. Huang, et al., Cancer Res. 76 (2016) 2076–2081.

  42. [42]

      S. Song, P. Peng, Z. Tang, et al., Sci. Rep. 7 (2017) 39858. doi: 10.1038/srep39858

  43. [43]

      F. Meric-Bernstam, R.F. Sweis, S. Kasper, et al., Clin. Cancer Res. 29 (2023) 110–121. doi: 10.1158/1078-0432.ccr-22-2235

  44. [44]

      B.C. Zhang, M.F. Laursen, L.L. Hu, et al., Nat. Commun. 15 (2024) 2760. doi: 10.1038/s41467-024-47046-5

  45. [45]

      S.S. Mayengbam, A. Singh, A.D. Pillai, M.K. Bhat, Transl. Oncol. 14 (2021) 101043. doi: 10.1016/j.tranon.2021.101043

  46. [46]

      I. Giacomini, F. Gianfanti, M.A. Desbats, et al., Front. Oncol. 11 (2021) 682911. doi: 10.3389/fonc.2021.682911

  47. [47]

      J.J. Repa, D.J. Mangelsdorf, Annu. Rev. Cell Dev. Biol. 16 (2000) 459–481. doi: 10.1146/annurev.cellbio.16.1.459

  48. [48]

      S.W. Altmann, H.R. Davis Jr., L.J. Zhu, et al., Science 303 (2004) 1201–1204. doi: 10.1126/science.1093131

  49. [49]

      X. Hu, F. Chen, L. Jia, et al., Cell 187 (2024) 1685–1700. e1618. doi: 10.1016/j.cell.2024.02.024

  50. [50]

      M. Sekiya, J. Osuga, M. Igarashi, et al., J. Atheroscler. Thromb. 18 (2011) 359–364. doi: 10.5551/jat.7013

  51. [51]

      J. Luo, H. Yang, B.L. Song, Nat. Rev. Mol. Cell Biol. 21 (2020) 225–245. doi: 10.1038/s41580-019-0190-7

  52. [52]

      C. Guo, Z. Chi, D. Jiang, et al., Immunity 49 (2018) 842–856 e847. doi: 10.1016/j.immuni.2018.08.021

  53. [53]

      M.S. Brown, A. Radhakrishnan, J.L. Goldstein, Annu. Rev. Biochem. 87 (2018) 783–807. doi: 10.1146/annurev-biochem-062917-011852

  54. [54]

      N. Zelcer, C. Hong, R. Boyadjian, P. Tontonoz, Science 325 (2009) 100–104. doi: 10.1126/science.1168974

  55. [55]

      S.B. Widenmaier, N.A. Snyder, T.B. Nguyen, et al., Cell 171 (2017) 1094–1109 e1015. doi: 10.1016/j.cell.2017.10.003

  56. [56]

      J. Garcia-Bermudez, L. Baudrier, E.C. Bayraktar, et al., Nature 567 (2019) 118–122. doi: 10.1038/s41586-019-0945-5

  57. [57]

      R. Wang, A. Hussain, Q. Guo, M. Ma, Crit. Rev. Oncol. Hematol. 193 (2024) 104194. doi: 10.1016/j.critrevonc.2023.104194

  58. [58]

      C.A. Lewis, C. Brault, B. Peck, et al., Oncogene 34 (2015) 5128–5140. doi: 10.1038/onc.2014.439

  59. [59]

      N.S. Tan, M. Vazquez-Carrera, A. Montagner, et al., Prog. Lipid Res. 64 (2016) 98–122. doi: 10.1016/j.plipres.2016.09.001

  60. [60]

      M.P. Plebanek, Y. Xue, Y.V. Nguyen, et al., Sci. Immunol. 9 (2024) eadi4191. doi: 10.1126/sciimmunol.adi4191

  61. [61]

      S.T. Yang, A.J.B. Kreutzberger, J. Lee, et al., Chem. Phys. Lipids 199 (2016) 136–143. doi: 10.1016/j.chemphyslip.2016.05.003

  62. [62]

      P. Varshney, V. Yadav, N. Saini, Immunology 149 (2016) 13–24. doi: 10.1111/imm.12617

  63. [63]

      A. Plociennikowska, A. Hromada-Judycka, K. Borzecka, K. Kwiatkowska, Cell. Mol. Life Sci. 72 (2015) 557–581. doi: 10.1007/s00018-014-1762-5

  64. [64]

      T.H. Tsai, S.F. Chen, T.Y. Huang, et al., Shock 35 (2011) 92–99. doi: 10.1097/SHK.0b013e3181ea45ca

  65. [65]

      J. Zhang, S. Yu, Q. Peng, et al., Cancer Biol. Med. 21 (2024) 45–64. doi: 10.3390/su17010045

  66. [66]

      X. Yu, S. Pan, Rev. Cardiovasc. Med. 25 (2024) 135. doi: 10.31083/j.rcm2504135

  67. [67]

      Z. Tian, Y. Zeng, Y. Peng, et al., Front. Immunol. 13 (2022) 996663. doi: 10.3389/fimmu.2022.996663

  68. [68]

      X. Tu, T.T. Chu, D. Jeltema, et al., Nat. Commun. 13 (2022) 6977. doi: 10.1038/s41467-022-33765-0

  69. [69]

      S.D. Clarke, Br. J. Nutr. 83 (2000) S59–S66. doi: 10.1017/s0007114500000969

  70. [70]

      I.K. Vila, H. Chamma, A. Steer, et al., Cell Metab. 34 (2022) 125. doi: 10.1016/j.cmet.2021.12.007

  71. [71]

      E. Berson, P. Chung, C. Espinosa, et al., Nat. Methods 21 (2024) 1400–1402. doi: 10.1038/s41592-024-02351-1

  72. [72]

      B. Zhao, X. He, J. Wu, S. Yan, BMC Cardiovasc. Disord. 20 (2020) 282. doi: 10.1186/s12872-020-01566-2

  73. [73]

      J. Shi, P.W. Kantoff, R. Wooster, O.C. Farokhzad, Nat. Rev. Cancer 17 (2017) 20–37. doi: 10.1038/nrc.2016.108

  74. [74]

      I.I. Lungu, A.M. Grumezescu, A. Volceanov, E. Andronescu, Molecules 24 (2019) 3547. doi: 10.3390/molecules24193547

  75. [75]

      Y. Huai, M.N. Hossen, S. Wilhelm, et al., Bioconjug. Chem. 30 (2019) 2247–2263. doi: 10.1021/acs.bioconjchem.9b00448

  76. [76]

      X. Hu, T. Wu, Y. Bao, Z. Zhang, J. Control. Release 256 (2017) 26–45. doi: 10.1016/j.jconrel.2017.04.026

  77. [77]

      M.J. Mitchell, M.M. Billingsley, R.M. Haley, et al., Nat. Rev. Drug Discov. 20 (2021) 101–124. doi: 10.1038/s41573-020-0090-8

  78. [78]

      H. Kim, E.H. Kim, G. Kwak, et al., Int. J. Mol. Sci. 22 (2020) 14. doi: 10.3390/ijms22010014

  79. [79]

      A.J.P. Teunissen, M.E. Burnett, G. Prevot, et al., Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 13 (2021) e1719. doi: 10.1002/wnan.1719

  80. [80]

      X. Han, M.G. Alameh, K. Butowska, et al., Nat. Nanotechnol. 18 (2023) 1105–1114. doi: 10.1038/s41565-023-01404-4

  81. [81]

      H.B.T. Moran, J.L. Turley, M. Andersson, E.C. Lavelle, Biomaterials 184 (2018) 1–9. doi: 10.1016/j.biomaterials.2018.08.054

  82. [82]

      J.K. Crane, Immunol. Invest. 49 (2020) 794–807. doi: 10.1080/08820139.2020.1776724

  83. [83]

      D. Cen, Q. Ge, C. Xie, et al., Adv. Mater. 33 (2021) e2104037. doi: 10.1002/adma.202104037

  84. [84]

      M. Luo, H. Wang, Z. Wang, et al., Nat. Nanotechnol. 12 (2017) 648–654. doi: 10.1038/nnano.2017.52

  85. [85]

      D.W. Zheng, F. Gao, Q. Cheng, et al., Nat. Commun. 11 (2020) 1985. doi: 10.1038/s41467-020-15927-0

  86. [86]

      N. Hoshyar, S. Gray, H. Han, G. Bao, Nanomedicine 11 (2016) 673–692. doi: 10.2217/nnm.16.5

  87. [87]

      J.A. Champion, S. Mitragotri, Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 4930–4934. doi: 10.1073/pnas.0600997103

  88. [88]

      A. Garapaty, J.A. Champion, PLoS One 14 (2019) e0217022. doi: 10.1371/journal.pone.0217022

  89. [89]

      H.R. Jin, J. Wang, Z.J. Wang, et al., J. Hematol. Oncol. 16 (2023) 103. doi: 10.1117/12.2689097

  90. [90]

      C. Liu, H. Chen, B. Hu, et al., Front. Pharmacol. 14 (2023) 1188926. doi: 10.3389/fphar.2023.1188926

  91. [91]

      L. Miao, C. Lu, B. Zhang, et al., J. Transl. Med. 22 (2024) 229. doi: 10.1186/s12967-024-05033-w

  92. [92]

      W. Mao, Y. Cai, D. Chen, et al., JCI Insight 7 (2022) e161940. doi: 10.1172/jci.insight.161940

  93. [93]

      M. Rehman, N. Tahir, M.F. Sohail, et al., Pharmaceutics 16 (2024) 1376. doi: 10.3390/pharmaceutics16111376

  94. [94]

      J. Yang, H. Zeng, Y. Luo, et al., Polymers 16 (2024) 2606. doi: 10.3390/polym16182606

  95. [95]

      Y. Duan, A. Dhar, C. Patel, et al., RSC Adv. 10 (2020) 26777–26791. doi: 10.1039/d0ra03491f

  96. [96]

      I. Waheed, A. Ali, H. Tabassum, et al., Front. Oncol. 14 (2024) 1296091. doi: 10.3389/fonc.2024.1296091

  97. [97]

      M. Niedzielski, M. Broncel, P. Gorzelak-Pabis, E. Wozniak, Biomed. Pharmacother. 129 (2020) 110388. doi: 10.1016/j.biopha.2020.110388

  98. [98]

      K. Musunuru, Annu. Rev. Med. 72 (2021) 447–458. doi: 10.1146/annurev-med-080819-044918

  99. [99]

      Y.M. Cheung, R. O'Brien, E.I. Ekinci, Intern. Med. J. 49 (2019) 1472–1480. doi: 10.1111/imj.14291

  100. [100]

       M. Banach, D.P. Mikhailidis, Cardiol. Clin. 36 (2018) 225–231.

  101. [101]

       A. Nenna, F. Nappi, D. Larobina, et al., Polymers 13 (2021) 711. doi: 10.3390/polym13050711

  102. [102]

       K. Sharma, K. Kumar, N. Mishra, Drug Deliv. 23 (2016) 694–709.

  103. [103]

       K. Sharma, S.S. Hallan, B. Lal, et al., Artif. Cells Nanomed. Biotechnol. 44 (2016) 1448–1456. doi: 10.3109/21691401.2015.1041637

  104. [104]

       R. Tiwari, K. Pathak, Int. J. Pharm. 415 (2011) 232–243. doi: 10.1016/j.ijpharm.2011.05.044

  105. [105]

       Z. Zhang, H. Bu, Z. Gao, et al., Int. J. Pharm. 394 (2010) 147–153. doi: 10.1016/j.ijpharm.2010.04.039

  106. [106]

       M. Yadav, N. Schiavone, A. Guzman-Aranguez, et al., Drug Deliv. Transl. Res. 10 (2020) 1531. doi: 10.1007/s13346-020-00777-6

  107. [107]

       Z. Li, W. Tao, D. Zhang, et al., Asian J. Pharm. Sci. 12 (2017) 285–291.

  108. [108]

       M.A. Shaker, H.M. Elbadawy, S.S. Al Thagfan, M.A. Shaker, Int. J. Pharm. 592 (2021) 120077. doi: 10.1016/j.ijpharm.2020.120077

  109. [109]

       Q. Wang, Z. Ren, J. Zhao, et al., Int. J. Med. Sci. 21 (2024) 2613–2622. doi: 10.7150/ijms.102328

  110. [110]

       H. Kim, S. Kumar, D.W. Kang, et al., ACS Nano 14 (2020) 6519–6531. doi: 10.1021/acsnano.9b08216

  111. [111]

       T. Jiang, L. Xu, M. Zhao, et al., Biomaterials 280 (2022) 121324. doi: 10.1016/j.biomaterials.2021.121324

  112. [112]

       K. Park, J. Control. Release 307 (2019) 423. doi: 10.1016/j.jconrel.2019.07.008

  113. [113]

       X. Zhang, X. Yang, Y. Wang, et al., Chin. Chem. Lett. 36 (2025) 109854. doi: 10.1016/j.cclet.2024.109854

  114. [114]

       H. Jiang, D. Liu, J. Wang, et al., J. Mater. Chem. B 12 (2024) 8616–8625. doi: 10.1039/d4tb01343c

  115. [115]

       A. Hu, L. Sun, H. Lin, et al., Signal Transduct. Target. Ther. 9 (2024) 68. doi: 10.1038/s41392-024-01765-9

  116. [116]

       Z. Fang, X. Zhang, H. Huang, J. Wu, Chin. Chem. Lett. 33 (2022) 1693–1704. doi: 10.1016/j.cclet.2021.11.050

  117. [117]

       Z. Xie, G. Zhang, Y. Meng, et al., Chin. Chem. Lett. 35 (2024) 109584. doi: 10.1016/j.cclet.2024.109584

  118. [118]

       J. Guo, M. Gu, Y. Chen, et al., Chin. Chem. Lett. 36 (2025) 110849. doi: 10.1016/j.cclet.2025.110849

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  Figure 1  The diagram shows the process of the cGAS-STING pathway. When DNA from infections, cell stress, or tumors enters the cytoplasm, it activates the enzyme cGAS. cGAS then produces cGAMP, which binds to STING protein in the ER. STING moves to the Golgi and triggers other proteins, like TBK1 and IRF3, to activate. These proteins then enter the nucleus, turning on genes that lead to an immune response, producing molecules like interleukin 2 (IL-2) and IL-6 to fight off infections or tumors. IKK, inhibitor of kappaB kinase; cGAMP, cyclic GMP-AMP; GTP, guanosine triphosphate; ATP, adenosine triphosphate; IκBα, inhibitory subunit of NF kappa B alpha; NF-κB, nuclear factor kappa-B; ISGs, interferon-stimulated genes.

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  Figure 2  Interaction between cholesterol metabolism and the STING pathway. Cholesterol is transported from the lysosome by NPC1, influencing STING activation in the ER. STING then translocates to the Golgi, where it activates IRF3, leading to IFN production. Cholesterol regulates this process through molecules like SOAT1 and SCAP-SREBP2, which can either promote or inhibit STING activation and signaling. The diagram highlights cholesterol's role in regulating both metabolism and immune responses.

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  Figure 3  The figure illustrates the relationship between the activation level of the STING pathway and different therapeutic strategies. The vertical axis represents the level of STING activation, ranging from insufficient activation to proper activation and over-activation. The horizontal axis represents the intervention strategies.

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  Figure 4  The image illustrates how nanomaterials can be used to enhance drug delivery, specifically targeting cholesterol reduction and promoting STING pathway activation for innate immune responses. (a) Different nanomaterials (polysaccharides, lipids, polymers, metals, and nucleic acids) can be tailored by shape, size, and charge to optimize delivery. (b) Strategy for statins as hydrophobic fragments for amphiphilic polymer preparation and self-assembly into NPs. (c) Strategy for statins as hydrophobic drugs encapsulated inside NPs. (d) Various nanomaterial shapes (sphere, rod, sheet) can improve mucus infiltration and receptor activation, further enhancing the drug's efficacy.

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  Table 1.  Overview of STING agonists, their example drugs, and mechanism descriptions.

  Category	Example drugs	Description	Ref.
  Synthetic CDNs	ADU-S100	First STING agonist in human clinical trials. Showed good tolerability in advanced tumors	[27]
  	IACS-8779, IACS-8803	Potent CDN STING agonists with targeted modifications. Demonstrated superior anti-tumor responses in melanoma models	[28]
  	MK-1454	Synthetic CDN analog for advanced/metastatic solid tumors or lymphomas. Showed good activity and safety in phase Ⅰ trials	[27]
  DMXAA and analogs	DMXAA (ASA404, Vadimezan)	Induces apoptosis in tumor endothelial cells, disrupts tumor vascular system, and activates innate immune system	[29]
  Small molecule agonists	diABZI	First effective non-nucleotide STING agonist. Enhances binding affinity and induces CD8+ T cell responses	[30]
  	SR-717	Orally available non-nucleotide STING agonist with concomitant induction of PD-L1 expression	[31]
  	MSA-2	Orally available, weakly acidic, non-nucleotide STING agonist that activates as homodimers	[32]

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