The Emerging Role of Nanocarrier-Based Delivery Systems for cGAS-STING Activation in Cancer Immunotherapy

Introduction

Malignant tumors are major diseases that seriously threaten human health. The 5-year survival rate of many solid tumors has remained stagnant for a long time, posing a severe challenge to clinical practice. Particularly challenging is that many tumors exhibit typical immunosuppressive phenotypic characteristics - a severe lack of cytotoxic T lymphocytes in the tumor microenvironment, significantly impaired antigen-presenting function, and a rich variety of immunosuppressive cell populations.¹ The unique immunosuppressive characteristics of this microenvironment directly leads to the unsatisfactory objective response rate of immune checkpoint inhibitors represented by PD-1/PD-L1 inhibitors in some patients, seriously restricting the clinical therapeutic effect.^2,3

At present, the treatment strategies for immunosuppressive tumors mainly face the following bottlenecks: The mechanism of action of existing immunotherapeutic strategies relies on pre-existing tumor-specific T cells.⁴ However, in the immune desert phenotype, due to the defect of antigen presentation mechanism, abnormal secretion of chemokines, and the formation of immunosuppressive networks, naive T cells fail to become activated and are unable to infiltrate the tumor site.⁵ Although existing treatment methods such as radiotherapy and chemotherapy can control tumor progression to a certain extent, it is difficult to fundamentally reverse the immunosuppressive microenvironment.⁶ Therefore, although immunotherapy, which recognizes and eliminates cancer cells through the immune system, can significantly reduce the side effects of traditional therapies, its clinical efficacy remains constrained by the deficiencies of existing targets. Identifying new immunotherapy targets is crucial for breaking through the current bottlenecks in cancer treatment.⁷

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a natural immune signaling pathway. Its activation leads to the secretion of type I interferon (IFN) to promote dendritic cell (DC) maturation, subsequently increasing immune cell infiltration into the tumor microenvironment (TME), thereby initiating an anti-tumor immune response in vivo.⁸ The cGAS-STING pathway, by specifically targeting tumor cells and initiating anti-tumor immune responses in vivo, has become a new strategy to enhance anti-tumor immunity. However, the STING activator cGAMP is a dinucleotide prone to enzymatic degradation in the blood; it typically does not target tumors and is easily degraded in vivo, limiting its clinical application.^9,10 Therefore, researchers employ carriers or chemical modifications to protect STING activators, thereby conferring higher enzymatic stability.

Nano-drug delivery systems are drug delivery platforms based on nanoparticle carriers, usually made from lipids, polymers, inorganic materials, or biological materials, with sizes generally between 1–200 nm.¹¹ Their characteristic is to achieve precise delivery and controlled release by encapsulating, loading, or binding drugs onto nanoparticles and endowing them with targeting and functionality through surface modification, thereby achieving efficient treatment.¹¹ Nano-DDS can selectively accumulate in tumor tissue through the enhanced permeability and retention (EPR) effect in cancer therapy and utilize their stimulus responsiveness to release drugs in specific microenvironments, reducing side effects on normal cells.¹² Therefore, nanoparticles offer significant advantages for delivering activators of the cGAS-STING pathway, improving therapeutic efficacy and reducing side effects. Through targeted design of nanoparticles, cGAS-STING activators can be precisely delivered to tumor tissue or immune cells, reducing the impact on healthy tissues and thus lowering systemic toxicity. This article systematically reviews the cutting-edge progress of cGAS-STING combined with nanomaterials in the diagnosis and treatment of oral cancer, analyzes its mechanism of action and clinical challenges, and prospects future directions for interdisciplinary collaborative innovation to promote the development of precision medicine for oral cancer.

cGAS-STING Pathway Structure and Activation Mechanism

The cGAS-STING pathway is a key signaling pathway in the innate immune system that recognizes cytoplasmic DNA and initiates immune responses. This pathway consists of two core proteins: cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING).¹³ cGAS, as a DNA sensor, has a structure that contains an N-terminal disordered region, a DNA-binding domain, and a C-terminal catalytic domain, enabling non-specific binding to double-stranded DNA (dsDNA) in the cytoplasm.¹⁴ When dsDNA released from tumors, viruses, bacteria, or damaged mitochondria binds to cGAS, it induces cGAS dimerization or oligomerization, exposing the catalytic active site, which then uses ATP and GTP to synthesize the second messenger 2′,3′-cGAMP.¹⁵ STING, as an endoplasmic reticulum transmembrane protein, consists of an N-terminal transmembrane region, a central linker region, and a C-terminal ligand-binding domain, usually existing as a dimer.¹⁶ When cGAMP binds to STING, it causes a conformational change in STING, transporting it from the endoplasmic reticulum to the Golgi apparatus and recruiting TANK-binding kinase 1 (TBK1) to form the STING-TBK1 signaling complex.¹⁷

The formation of the STING-TBK1 complex is a key step in initiating downstream signal transduction. After TBK1 activates through autophosphorylation, it further phosphorylates the C-terminal domain of STING, providing a binding site for the recruitment of interferon regulatory factor 3 (IRF3).¹⁸ Phosphorylated IRF3 forms dimers and translocates to the nucleus, initiating the transcription of type I interferons (IFN-α/β) and interferon-stimulated genes (ISGs).¹⁹ Simultaneously, STING can also activate the NF-κB signaling pathway through tumor necrosis factor receptor-associated factor 6 (TRAF6), promoting the production of pro-inflammatory cytokines.²⁰ These immune molecules together constitute an anti-viral and anti-tumor immune defense network, which can not only directly inhibit pathogen replication but also activate immune cells such as NK cells and DCs, enhancing the body’s immune surveillance function.^21,22 Figure 1 depicts the molecular mechanisms of the cGAS-STING Pathway.

Figure 1 Schematic diagram of the molecular mechanism of the cGAS-STING signaling pathway in innate immunity for detecting cytoplasmic DNA.

The activity of the cGAS-STING pathway is finely regulated at multiple levels to avoid tissue damage caused by excessive immune responses. At the molecular level, the cytoplasmic nuclease Trex1 can degrade free DNA, preventing sustained cGAS activation.²³ E3 ubiquitin ligase RNF5-mediated ubiquitination and degradation of STING can terminate signal transduction; autophagy-related proteins such as ULK1 can also negatively regulate STING activity.^24,25 Pathologically, functional defects in this pathway may lead to viral infection or tumor immune escape.^26,27

Key Role of cGAS-STING Signal Transduction in Tumors

The cGAS-STING pathway is a key cytoplasmic DNA sensing mechanism that connects innate immunity with anti-tumor immune responses. Under pathological conditions such as genomic instability, mitochondrial damage, viral/bacterial infection, or cellular stress, accumulated dsDNA in the cytoplasm can be recognized by cGAS.²⁸ As detailed in Section 2, activation of the cGAS-STING pathway triggers type I interferon production and pro-inflammatory cytokines, which play key roles in anti-tumor immunity. IFN-β plays a key role in activating tumor-specific T cells, thereby linking innate immune sensing with adaptive anti-tumor immunity. Due to its ability to recognize abnormal cytoplasmic DNA and initiate robust immune activation, cGAS-STING has become a key target for enhancing cancer immunotherapy.⁸ Simultaneously, this pathway helps activate dendritic cells, T cells, and natural killer cells, enhancing anti-tumor immune responses.²⁹ The pathway can also promote apoptosis and senescence of cancer cells, enhancing the protective effects of cytotoxic T cells and natural killer cells.¹⁴ Activation of the cGAS-STING pathway can improve the efficacy of immune checkpoint inhibitors and other immunotherapies. Mechanistically, cGAS-STING signaling can promote antigen presentation, enhance T cell infiltration, and reduce immunosuppressive cell populations, thereby overcoming key resistance mechanisms in immunotherapy. Preclinical and clinical evidence indicate that combining cGAS-STING agonists with ICIs can significantly improve treatment efficacy while reducing the risk of primary and acquired resistance, providing new strategies to expand the clinical benefits of cancer immunotherapy.³⁰

First, the cGAS-STING pathway prevents cancer cell proliferation through the DNA damage response (DDR) and senescence-associated secretory phenotype (SASP); second, STING induces autophagy to clear DNA from the cytoplasm, preventing excessive immune activation; furthermore, the cGAS-STING pathway also promotes cancer cell apoptosis by upregulating pro-apoptotic proteins and downregulating anti-apoptotic proteins.^31–34 Simultaneously, the cGAS-STING pathway enhances T cell anti-tumor responses by activating DCs and natural NK cells, promoting the generation of tumor-specific immune responses.³⁵ These mechanisms work together, making the cGAS-STING pathway play a key role in anti-tumor immunity, providing new strategies and targets for cancer immunotherapy. Activation of the cGAS-STING pathway can enhance tumor immune surveillance, promote anti-tumor T cell responses, and improve the immune microenvironment of tumors by inducing the production of immune mediators such as interferons.³⁶ These mechanisms are crucial for the treatment of tumors, as the disease is often difficult to treat due to immune escape. However, although activation of the cGAS-STING pathway can promote immune responses, some tumor cells can evade the activity of this pathway through various mechanisms. For example, tumors may evade the effect of this pathway by deleting the STING gene, inhibiting cGAS activity, or upregulating immune escape factors, thereby avoiding immune surveillance and attack.³⁷ To overcome this immune escape mechanism, researchers have proposed the possibility of combination immunotherapy. Using STING agonists to directly activate the cGAS-STING pathway can not only enhance immune responses in the tumor microenvironment but also be used in combination with immune checkpoint inhibitors to further improve the effectiveness of immunotherapy.³⁸ Through this combination therapy, T cells can be activated and the immune response to tumor cells enhanced, thereby overcoming tumor immune escape and improving treatment efficacy.³⁹ In summary, the cGAS-STING pathway plays a role in promoting immune clearance in the tumor immune response. The treatment strategy combining STING agonists with immune checkpoint inhibitors provides new therapeutic perspectives and potential breakthroughs for tumor immunotherapy.

STING Agonists and Nanomaterial-Based Delivery/Activation Strategies

As an important breakthrough in the field of tumor immunotherapy, STING agonists are currently mainly divided into two categories: cyclic dinucleotides (CDNs) and their derivatives, and non-nucleotide agonists.⁴⁰ Among CDN derivatives, endogenous 2′,3′-cGAMP and its analogs ADU-S100 (MIW815) and MK-1454 have entered clinical research stages. These compounds exert anti-tumor effects by mimicking natural second messengers.^41,42 Among them, ADU-S100 has shown encouraging therapeutic effects in clinical trials for solid tumors like melanoma. On the other hand, non-nucleotide agonists include synthetic small molecules and specific metal ions. This type of agonist has attracted much attention due to its unique chemical structure and mechanism of action⁴³(Table 1).

Table 1 STING Agonists in Clinical Trials and Their Combinations

The clinical application of STING agonists faces a series of key challenges. Natural cyclic dinucleotide agonists like cGAMP exhibit significant pharmacokinetic defects; their phosphodiester backbone is readily degraded by the extracellular enzyme ENPP1, while their strong polarity limits cell membrane permeability, significantly limiting bioavailability.⁵⁵ Furthermore, lack of tumor-specific targeting during systemic administration may cause systemic immune overactivation, leading to severe dose-limiting toxicity.⁵⁶ These fundamental problems prompt researchers to seek breakthroughs from both molecular design and delivery technology dimensions, providing clear research directions for subsequent nanocarrier development and structural optimization. Current research hotspots focus on the optimization of agonist delivery systems, including the development of nanocarrier technology and targeted delivery strategies. These innovative methods significantly improve drug accumulation in tumors and therapeutic effects. In terms of clinical translation, STING agonists not only show therapeutic potential as single agents, but combination regimens with immune checkpoint inhibitors show even more synergistic effects.^57,58 New-generation STING agonists have achieved significant breakthroughs in stability and selectivity through structural optimization, providing new intervention means for tumor immunotherapy.⁵⁸ These advances make STING agonists one of the most potential research directions in the field of tumor immunotherapy.

CDNs and Their Derivatives

CDNs are natural immune signaling molecules formed by the cyclization of two nucleotides via phosphodiester bonds. 2′,3′-cGAMP is the natural STING ligand synthesized by mammalian cells after cGAS recognizes cytoplasmic DNA. 2′,3′-cGAMP activates the STING pathway via the canonical mechanism described in Section 2, leading to type I interferon expression and anti-tumor immunity. Besides mammals, bacteria can also secrete natural CDNs, including c-di-GMP (cyclic diguanylate monophosphate), c-di-AMP (cyclic diadenylate monophosphate), and cAMP-GMP (cyclic adenosine monophosphate–guanosine monophosphate), which can activate the host’s STING pathway.⁵⁹ Recent research discovered a novel 2′,3′-cGAMP STING agonist compound-8d, which exhibits higher binding affinity to human STING compared to mammalian CDN-2′3′-cGAMP and strongly triggers the expression of type I IFN and pro-inflammatory cytokines.⁶⁰ Besides natural CDNs, there are also a series of synthetic CDN derivatives. The first CDN derivative to enter clinical trials, ADU-S100, activates STING in the tumor microenvironment, inducing a strong anti-tumor immune response, including CD8+ T cell activation and tumor regression, demonstrating superior STING activation ability compared to natural CDNs. When combined with immune checkpoint inhibitors, it shows enhanced anti-tumor effects.⁴⁹ As the first intravenous STING agonist—MK-1454, when injected into immunocompetent mice with syngeneic tumors, it showed robust tumor cytokine upregulation and effective anti-tumor activity. Furthermore, combination therapy with the anti-mouse PD-1 antibody mDX400 in animal models further enhanced tumor shrinkage in models intrinsically resistant to monotherapy.⁴¹ Recent research identified a CDN derivative specifically designed for human STING——IMSA101, that avoids responses in mouse models, which is significant for human clinical application⁶¹ Meanwhile, IMSA101 can continuously induce IFN-β for over 72 hours after subcutaneous injection. This long-lasting interferon induction helps maintain a sustained immune response, enhancing the anti-tumor effect.⁴⁵ Although CDNs and their derivatives show the aforementioned significant potential in anti-tumor immunotherapy, their clinical application still faces multiple challenges. Pharmacokinetic defects are a major limitation; natural CDNs are easily degraded by extracellular nucleases, with a plasma half-life of less than 5 minutes. Even thiophosphorylated derivatives struggle to break the stability bottleneck of a few hours.^42,62 Delivery obstacles are equally prominent; these large negatively charged molecules have difficulty penetrating cell membranes, tumor accumulation rates are generally low upon systemic administration, and intratumoral injection cannot cover metastatic lesions.⁹

Non-CDN Agonists

Current research on non-CDN classes is also very active. Compared to traditional CDN agonists, non-CDN agonists have advantages: (1) They have significantly improved physicochemical properties, enabling effective anti-tumor activity through oral administration, and greatly enhanced chemical stability, allowing long-term storage at room temperature, completely overcoming the limitations of CDNs requiring low-temperature storage and injection administration.⁶³ (2) Through ingenious molecular design, they can specifically recognize different human STING haplotypes and stabilize the STING dimerization intermediate state, extending signal activation time to 72 hours (CDNs typically <12 hours), while avoiding false positive interference in preclinical models like mice.^61,64 (3) Small molecule agonists significantly activate the STING signaling pathway by directly binding and stabilizing the STING protein, and show good anti-tumor effects and tolerance in mouse tumor models.⁶⁵ They can also be rationally designed to construct bifunctional molecules that simultaneously activate pathways and degrade negative regulators.⁶⁶ These advantages make non-nucleotide agonists a key driving force for the development of STING-targeted therapy towards precision and convenience.

As the first non-nucleotide STING agonist——DMXAA, can induce the production of tumor necrosis factor, serotonin, and nitric oxide, leading to tumor hemorrhagic necrosis.⁴⁷ The oral non-CDN agonist MSA-2 can bind to STING in a non-covalent dimer form, has nanomolar affinity, and increases cellular uptake and retention in the acidic tumor microenvironment, thereby enhancing anti-tumor efficacy, overcoming the limitations of traditional CDN agonists.⁴⁸ SR-717 is a non-nucleotide small molecule STING agonist targeting the cGAS-STING pathway in THP1 cells. It can directly activate the STING pathway by mimicking the “closed” conformation of the natural STING ligand cGAMP, thereby promoting the activation of CD8+ T cells, natural killer cells, and dendritic cells, and promoting antigen cross-priming, thus enhancing anti-tumor immune responses. It can also induce the expression of clinically relevant targets like PD-L1 through a STING-dependent mechanism.^43,56 In recent research, VB-85247 is a novel non-CDN agonist for treatment via intravesical administration to provide sustained exposure time to bladder cancer cells while avoiding potential problems associated with intratumoral injection of STING agonists. The effective dose was well tolerated and induced an immune response with immune memory, preventing rechallenge without further treatment.⁵⁰

Besides the aforementioned non-nucleotide agonists, metal ions have also been proven to be a class of potential STING agonists, particularly Mn²⁺, which were found to significantly enhance the activation of the STING pathway, promote the production of type I interferon (IFN-I), thereby promoting the maturation of DCs and the infiltration of antigen-specific T cells, thus enhancing anti-tumor immune responses.⁵¹ Besides Mn²⁺, Zn²⁺ are also common metal ion agonists. Zn²⁺ enhances the activity of the cGAS enzyme directly, by promoting phase separation of cGAS from DNA, helping it faster convert intracellular DNA danger signals into the immune signaling molecule cGAMP, thereby activating innate immune signaling.⁵² Besides the aforementioned metal ions that directly activate the STING pathway, there are also metal ions that indirectly activate it. For example, Cu²⁺ overload causes mitochondrial damage in astrocytes, leading to mitochondrial DNA leakage into the cytoplasm and activation of the cGAS-STING pathway, causing an immune response.⁵³ Recent research shows that anions can also act as STING agonists to activate the cGAS-STING pathway. For instance, MoO₄²⁻ can effectively activate the cGAS enzyme, enhancing its ability to detect abnormal DNA, thereby improving cGAMP production efficiency. Meanwhile, the slow release and intracellular accumulation characteristics of MoO₄²⁻ enable it to continuously activate the cGAS-STING pathway, promote type I interferon secretion, and enhance anti-tumor immune responses.⁵⁴ MoO₄²⁻ to further amplify the activation of the STING pathway, forming a mechanism that significantly inhibits tumor growth and metastasis.⁶⁷

Although non-CDN agonists like MSA-2 exhibit superior immune activation capabilities in tumors, the challenge of balancing efficacy and toxicity remains the primary limitation. Systemic administration may lead to excessive immune activation, resulting in systemic inflammation and cytokine release syndrome (CRS), with grade 3–4 fever and hepatotoxicity events observed clinically.^68,69 Simultaneously, some non-CDN agonists may unexpectedly activate other immune pathways, such as TLR4, which could lead to undesired immune responses, causing overstimulation of the immune system, subsequently leading to decreased immune cell function, ie, immune exhaustion, and also promoting tumor metastasis.⁶⁶ The issue of insufficient tumor targeting is equally prominent and requires further modification and optimization.

Nanomaterials for the Delivery of Agonists

Nanomaterials, due to their unique properties such as high affinity, controlled release, targeting, and extended drug half-life, serve as ideal carriers or direct agonists for STING agonists. In recent years, nanotechnology has made significant progress. These technologies enable nanomaterials, after modification and optimization, to greatly improve drug solubility in water, extend half-life, and promote maximum therapeutic effects while minimizing adverse reactions.^70–72 Common nanomaterials include liposomes, polymeric nanoparticles, metal nanoparticles, and carbon-based nanomaterials. They can protect STING agonists from degradation and achieve precise delivery to tumors or infection sites, while maintaining long-term immune activation effects through sustained-release mechanisms (Table 2). Furthermore, the multifunctionality of nanomaterials allows them to be combined with other therapies to achieve synergistic treatment, significantly enhancing anti-tumor effects⁷³(Table 3).

Table 2 Nanomaterials Used for Delivering STING Agonists

Table 3 Comparison of Different Nanocarriers for STING Agonist Delivery

Lipid Nanoparticles

Lipid nanoparticles (LNPs) are nanoscale delivery systems composed of phospholipids, cholesterol, helper lipids, and polyethylene glycol (PEG)-modified lipids.¹³⁸ Their unique lipid bilayer structure can efficiently encapsulate various drug molecules, including small molecule drugs, nucleic acids, and proteins, while protecting the drugs from enzymatic degradation or clearance by the immune system.¹³⁹ LNPs have good biocompatibility and degradability. They can achieve controlled drug release by adjusting lipid composition and achieve specific delivery through surface modification with targeting ligands.^127,138 These properties make LNPs ideal carriers in the field of drug delivery, widely used in vaccine development, cancer treatment, and gene therapy. For example, efficiently formulating cGAS agonists with lipid nanoparticles enables the development of therapeutic agents for cancer immunotherapy, allowing for the efficient delivery of cGAS agonists to tissues, cells, and the cytoplasm.⁸⁰ Furthermore, by encapsulating the negatively charged STING agonist cGAMP in positively charged cationic liposomes, the cellular binding, endosomal uptake, and cytoplasmic delivery of cGAMP can be enhanced. Meanwhile, cationic liposomes have the ability to promote positive anti-tumor immune effects and can also be designed to selectively target the overexpression of mannose receptors in cancer and immune cells, including cationic particle charge and embedded muramyl dipeptide (MDP).⁷⁶

In response to the demand for tumor immunotherapy, researchers have further developed intelligent lipid nanoparticles based on manganese ions and their nanocomplexes. These nanoparticles can specifically release active components in response to the tumor microenvironment, thereby achieving precise activation of the cGAS-STING pathway and immune enhancement. Jiawei Sun et al created a novel manganese lipid nanoparticle (LNM). LNM can activate the cGAS-STING signaling pathway without the need for combination with chemotherapeutic drugs or other immune activators, inducing the production of pro-inflammatory cytokines, and inhibiting tumor development.⁷⁸ (As depicted in Figure 2.⁷⁸) Besides encapsulating Mn²⁺ alone, lipid nanoparticles can also encapsulate FePt alloy and MnO nanocrystals to prepare ALFM. ALFM responds to the weakly acidic tumor microenvironment and degrades, releasing FePt and Mn²⁺ ions. The released Mn²⁺ ions not only increase cellular ROS levels through Fenton-like reactions but also activate the cGAS-STING signaling pathway, stimulating anti-tumor immune responses.⁷⁴ These studies illustrate the evolutionary design of lipid nanoparticles—progressing from passive drug loading to active activation and environmental responsiveness—thereby significantly enhancing treatment specificity and efficacy.

Figure 2 The schematic illustration of Lipid nanoparticles (A) Preparation process of LNM nanoparticles. (B) Transmission electron microscopy (TEM) image of LNM nanoparticles. (C) Mn2⁺ content in MC38 cells at different time periods. (D) Expression of P-STING protein under the action of different concentrations of LNM. (E) Expression of P-IRF3 protein under the action of different concentrations of LNM. (F) Tumor volume in mice. (G) Tumor weight in mice. (H) Statistical analysis of CD8 T cell positive rate in mouse splenocytes. (I) Statistical analysis of CD4 T cell positive rate in mouse splenocytes. (J) Expression of IFN-γ in mouse serum. (K) Expression of IL-6 in mouse serum.(ns, no significance;*p < 0.05, **p < 0.01,***p < 0.001, ****p < 0.0001).78

The core mechanism of LNPs as nanoscale delivery systems lies in their ability to enrich at tumor or inflammation sites through the EPR effect and enter cells through endocytosis.^140,141 In the acidic environment of tumors, the lipid bilayer of LNPs undergoes structural changes, releasing drug molecules into the cytoplasm, thus achieving efficient delivery.¹⁴² Furthermore, liposomes can be functionalized with folate (FA) to enhance the accumulation and penetration of cGAS agonists in tumors, promote therapeutic effects, modulate the tumor microenvironment, and activate the cGAS-STING innate immune signaling pathway to improve immune function.¹⁴³

To further enhance the targeting and responsiveness, researchers have also developed lipid nanoparticles based on cell membrane mimetic technology, enabling precise responses to tumor lesions and specific therapeutic signals. Wei et al developed a biomimetic nano-drug delivery system called PB, which utilizes platelet membrane (PM) fused liposomes to load cGAS agonists. After intravenous administration, PB selectively targets cancer cells. Irradiation can further promote the accelerated release of cGAS agonists, activate the cGAS-STING pathway in cancer cells, and ultimately enhance radiotherapy outcomes and anti-tumor immune responses.⁷⁷ Zheng et al designed novel nanovesicles manufactured through hybridization of tumor cell membrane and phospholipids for the delivery of doxorubicin and reversine.¹²⁴ These studies collectively represent the evolution of lipid nanoparticle technology towards biomimetic intelligent delivery. By mimicking the characteristics of natural cells, they significantly enhance their active targeting ability and response performance to specific physical signals or biological environments.

Although LNPs show great potential in drug delivery and immunotherapy, they still have some limitations. First, the stability and drug loading efficiency of LNPs need further optimization to avoid drug leakage or degradation during delivery.¹⁴⁴ Second, LNPs may cause immunogenic reactions or toxicity, especially with long-term use or high doses, which may limit their clinical application.¹⁴⁵ Furthermore, the targeting of LNPs still needs improvement. Although surface modification can improve specificity, precise delivery remains challenging in the complex human environment.¹⁴⁶ Finally, the cost and technical difficulties of large-scale production are also important factors restricting their commercialization. Despite these shortcomings, nano-DDS loading cGAS agonists with LNPs still have broad prospects in the future. Through advances in materials science and nanotechnology, smarter and more stable LNP carriers can be developed to achieve precise release and efficient delivery of drugs.⁸²

Polymeric Nanoparticles

Polymeric nanoparticles (PNPs) also have significant potential in delivering cGAS-STING activators in tumor immunotherapy. Polymeric nanoparticles are nanoscale delivery systems formed from natural or synthetic polymers through methods such as self-assembly, emulsion polymerization, or nanoprecipitation, with particle sizes typically between 10–1000 nm.^147,148 The core structure of PNPs consists of polymer chains. Common polymer materials include polylactic acid (PLA), poly actic-co-glycolic acid (PLGA), polycaprolactone (PCL), polyethyleneimine (PEI), and polyethylene glycol (PEG).¹⁴⁹

The core mechanism of PNPs as nanoscale delivery systems lies in their ability to effectively deliver drugs to specific targets, improve drug stability, and control drug release.¹⁵⁰ Their design can overcome biological barriers by adjusting physicochemical properties, such as rapid clearance, complex hemodynamics, suboptimal biodistribution, etc.¹³⁰ Additionally, the sustained-release properties of PNPs can avoid side effects caused by drug burst release while maintaining long-term drug concentration and improving therapeutic efficacy.¹⁵¹ Mohamed et al used a polymer platform to deliver cGAMP into tumors and activate the STING pathway in the TME, exerting its immunotherapeutic function. As shown in Figure 3 It demonstrates the activation of the cGAS-STING pathway in PNPs and its inhibition of tumors.⁹⁶

Figure 3 (A) Schematic diagram of polymer nanoparticle synthesis. (B) TEM images of polymeric nanoparticles at pH 7.0 and pH 5.0. (C) pH-responsive cGAMP release kinetics of polymeric nanoparticles. (D) Nanoparticles promoted the ability of cGAMP to induce murine IFN‐β (mIFN‐β) in DC2.4 cells. (E) Nanoparticles outperformed controls to induce mIFN‐β) in DC2.4 cells. (F) The dose‐dependent cGAMP‐selective IFN response.(G) The superior INF induction ability of nanoparticles than controls. (H) Tumor volume in mice. (I and J) Representative flow cytometry plots (I) and quantification (J). (K) Tumor weight in mice.(ns, no significance;*p < 0.05, **p < 0.01,***p < 0.001, ****p < 0.0001).96

Metal NPs

Metal nanoparticles (MNPs) are nanoscale particles composed of metal elements such as gold, silver, iron, and platinum, with particle sizes typically between 1–100 nm. They possess unique physicochemical properties, such as surface plasmon resonance effects and superparamagnetism.^152,153 These properties give MNPs excellent performance in optics, magnetism, and catalysis, while also providing a foundation for their applications in biomedicine. The structures of MNPs are diverse, including spherical, rod-shaped, cubic, and core-shell structures. Their surfaces can be chemically modified to introduce functional molecules, thus achieving multifunctionality.¹⁵⁴ Furthermore, MNPs have high surface area and reactivity, enabling efficient loading of drug molecules or catalyzing chemical reactions, while also having good biocompatibility and degradability, making them ideal choices for nanoscale delivery systems.¹⁵⁵ Among many metal nanoparticles, manganese, as a STING agonist, activates the innate immune system in vivo through the cGAS-STING signaling pathway, therefore it is most commonly used in the construction of metal nanoparticles. Zhu et al developed a manganese nanoplatform that integrates a micro-precipitated manganese ion core and a phospholipid bilayer shell. Then, co-loading of glucose oxidase and paclitaxel forms manganese-based nanoparticles. This nanoplatform showed good synergistic effects in the 4T1 tumor-bearing mouse model and significantly reduced the dosage of chemotherapeutic drugs.¹¹² Meng et al developed a novel delivery system based on a manganese-phenolic coordination network for loading the hydrophilic STING agonist ADU-S100. It is prepared by coordination-driven self-assembly of tannic acid and manganese ions, possessing unique pH/glutathione (GSH)-responsive degradation characteristics. It not only overcomes the stability challenges of STING agonists but also ensures efficient intracellular delivery. The core advantage of this system lies in its dual mechanism of action: the released ADU-S100 directly activates the STING pathway, while the synchronously released Mn²⁺ ions act as STING signal sensitizers, synergistically amplifying the immune activation effect.⁹⁷

Mn can also be used to construct nanoparticles with other metals.¹⁵⁶ Li et al constructed MnO₂-modified zeolitic imidazolate framework-8 nanoparticles. Due to the high expression of glutathione and low pH in tumors, ZIF-8@MnO₂ is decomposed to release Mn²⁺ and Zn²⁺ ions, inducing oxidative stress and cytoplasmic leakage of fragmented mitochondrial double-stranded DNA, further increasing the sensitivity of cGAS to dsDNA as an immunostimulatory signal.¹¹³ There are also CM NPs constructed with Mn and Ca, designed by Luo et al inspired by the biological functions of Ca²⁺ and Mn²⁺. They constructed a dual-iron overload nanoplatform (B16F10@CaCO₃--CU@MnO₂, called CM NPs) coated with B16F10 cell membrane. B16F10 cancer cell membrane-coated nanoparticles have active targeting ability, promoting efficient cellular uptake and tumor enrichment. pH-responsive released Ca²⁺ and Cu²⁺ induce intracellular calcium overload, triggering immunogenic cell death (ICD) and increased ROS, while Mn²⁺ remodels the TME by alleviating hypoxia and further amplifies ROS generation. Additionally, Mn²⁺ promotes immune cell proliferation and maturation, thereby activating systemic anti-tumor immunity. This dual-iron overload strategy exhibits excellent therapeutic effects. When combined with immune checkpoint inhibitors, it can markedly improve immune responses, providing a highly potential combination strategy for cancer treatment.¹⁰⁴

Besides Mn²⁺ directly activating the cGAS-STING signaling pathway as a STING agonist, some metal ions can also damage mitochondrial DNA (mtDNA), leading to cytoplasmic DNA leakage, thereby activating the cGAS-STING pathway. Yu et al designed a mitochondria-targeting ruthenium complex, whose molecular structure contains a β-carboline alkaloid-derived main ligand and a triphenylphosphine-modified alkyl chain auxiliary ligand. This special structure allows Ru1 to self-assemble into stable nanoparticles through multivalent intermolecular interactions. Notably, the high charge density of the triphenylphosphine group gives it the ability to specifically target mitochondria. Under photoactivation conditions, Ru1 can induce mitochondrial DNA damage, leading to the release of cytoplasmic double-stranded DNA, thereby effectively activating the cGAS-STING pathway.¹⁰¹ Furthermore, Zn²⁺ can also promote phase separation of the cGAS protein and enhance the enzymatic catalytic activity of cGAS. They can also cause the accumulation of endogenous ROS within cells. Excessive intracellular ROS may also lead to mitochondrial damage and the release of mtDN, which is a dsDNA. Zhang et al, inspired by the STING activation potential of Zn²⁺ and the natural COX-2 inhibitory properties of CPC, developed a novel nanoreactor system by integrating cyclopentyl carbamate into zinc-based metal-organic frameworks. The Zn²⁺ released after nanoparticle decomposition has a dual function: generating ROS to induce tumor cell apoptosis and activating the STING pathway to promote dendritic cell maturation and anti-tumor immunity. CPC can effectively inhibit the COX-2/PGE₂ pathway, reverse treatment-induced immunosuppression, and enhance Zn²⁺-mediated immune activation. The synergistic cytotoxic and immunomodulatory effects provide an innovative strategy for combined chemo-immunotherapy.¹¹⁰ (As depicted in Figure 4). Beyond serving as direct STING agonists for antitumor effects, manganese‑based nanoparticles can also enhance immunotherapy by modulating immune cell functions. A recent study repolarized neutrophils into an antitumor phenotype via MnO₂ nanoparticle‑activated STING pathway, significantly potentiating Salmonella‑mediated tumor immunotherapy.¹⁵⁷ This strategy offers a new perspective for manganese‑based nanomaterials in modulating the tumor immune microenvironment through STING pathway activation.

Figure 4 The schematic illustration of metal nanoparticles (A) Preparation process of metal nanoparticles. (B) Representative images of MDA-MB-231 cell clone formation under different treatments. (C and D) Representative images (C) and quantification (D) of DC maturation (CD80, CD86 of CD45 BMDCs) induced by supernatant from Zn2⁺-treated cancer cells. (E) Zn2⁺ concentration in mouse tumor tissue. (F) Tumor volume in mice. (G) Photographs of tumors excised from mice. (H) Tumor weight in mice.(*p < 0.05, **p < 0.01,***p < 0.001, ****p < 0.0001).110

MNPs as nano-DDS for cGAS agonists, although showing significant advantages in targeting, stimulus responsiveness, and multifunctionality, still have some limitations. First, the biocompatibility and long-term toxicity issues of MNPs have not been fully resolved. Some metal nanoparticles may be toxic to normal cells at high concentrations.¹⁵⁸ Second, the metabolism and clearance mechanisms of MNPs in vivo are not yet clear, which may lead to long-term accumulation and potential side effects.¹⁵⁹ Finally, the stability of MNPs may be affected by the complex in vivo environment; for example, protein adsorption may cause particle aggregation or functional loss.¹⁶⁰ Despite these challenges, the potential of MNPs in cGAS agonist delivery remains enormous. Future research should focus on developing safer metal nanomaterials and improving their biocompatibility and stability through surface modification. Simultaneously, optimize the preparation process of MNPs to achieve low-cost, large-scale production, and In-depth study their metabolism and clearance mechanisms in vivo to ensure the safety of their clinical application.

Mesoporous Silica NPs

Mesoporous silica nanoparticles (MSNs) are inorganic nanomaterials with a regular mesoporous structure, primarily composed of SiO₂. They possess highly ordered mesoporous channels, a large specific surface area, tunable pore size and pore volume, and excellent surface modification capability.¹³⁴ The specific surface area of MSNs usually exceeds 1000 m²/g, enabling them to efficiently load various hydrophilic or hydrophobic drugs, including small molecule chemotherapeutic drugs, genetic drugs, proteins, and immunomodulators.¹⁶¹ Furthermore, their surfaces are rich in silanol groups, which can be modified with targeting ligands, polymers, or responsive groups to achieve targeted transport and controlled release, improving the therapeutic effect of drugs. Compared to organic nano-DDS, the inorganic nature of MSNs has higher stability. They can slowly degrade into non-toxic Si(OH)₄ in physiological environments, metabolized and excreted by the body, exhibiting good biocompatibility and greatly reducing the potential toxicity issues that may arise from long-term accumulation.¹⁶²

As part of nano-drug delivery systems, MSNs show great potential in cancer treatment and immunotherapy due to their exceptional drug loading capacity, targeted delivery, and intelligent responsive release mechanisms. Their nanoscale size and modifiable surface functionality enable them to specifically enter tumor cells or immune cells through receptor-mediated endocytosis, thereby improving drug delivery efficiency.¹⁶³ Biodegradable PMMR@MH, after being internalized by tumor cells, decomposes in response to the acidic-reductive intracellular environment, rapidly releasing SR-717. Meanwhile, under glutathione (GSH)-rich conditions, the internal PMM slowly decomposes to perform sustained release of cisplatin and Mn²⁺. Under the sequential pre-activation by SR-717 and subsequently released Mn²⁺, cytosolic dsDNA fragments are easily recognized by cGAS in tumor cells and DCs, thus achieving cascade cGAS-STING activation to activate immune cells and amplify anti-tumor immune responses.¹¹⁶ (As depicted in Figure 5). Furthermore, MSNs often utilize their regular mesoporous structure, high specific surface area, and controllable size and morphology to guide the growth or coating of other materials, ultimately serving as templates for nanoparticle production, especially after removing the MSNs to form the target nanostructure. They are widely used in the preparation of nanomaterials with hollow structures or specific morphologies. For example, monodisperse H-MnO₂ with uniform morphology was synthesized by in situ growth of MnO₂ on solid silica nanoparticles, followed by removal of the silica core. Its interior shows abundant pores, remaining stable during surface modification and N-methyl-N-nitroaniline (NMA) loading processes.¹¹⁵

Figure 5 The schematic illustration of Mesoporous silica nanoparticles (MSNs) (A) Schematic diagram of mesoporous silica nanoparticle preparation. (B) Representative TEM images of mesoporous silica nanoparticles incubated for 12 and 72 h under different conditions. (C) Flow cytometry of 4T1 cell apoptosis after different treatments. (D) Flow cytometry analysis of mature DC cells after incubation with 4T1 cells subjected to different treatments. (E) Whole-animal in vivo bioluminescence images of 4T1 luciferase-expressing mice after different treatments. (F) Mesoporous silica nanoparticles increased the expression of IFN-β, IL-6, IFN-γ, and TNF-α in vivo. (G) Tumor volume change curves in mice under different treatments. (**p < 0.01,***p < 0.001, ****p < 0.0001).116

MSNs still have some limitations in loading cGAS agonists. First, the biodegradation rate of MSNs is relatively slow, which may lead to prolonged retention in vivo, potentially causing chronic inflammatory reactions or long-term accumulation risks.¹³⁵ Second, the strong negative charge on the MSN surface may affect interactions with cell membranes, reducing drug delivery efficiency. Therefore, further modification is usually needed to enhance targeting ability.¹⁶⁴ Furthermore, the loading and release mechanisms of cGAS agonists in MSNs still need optimization. Although their mesoporous structure can efficiently load cGAMP, how to precisely control its release in the tumor microenvironment or within immune cells remains a challenge. For example, some designs may lead to premature drug leakage or insufficient release before lysosomal degradation, affecting immune activation.¹⁶⁵ Simultaneously, the immunogenicity and in vivo metabolic pathways of MSNs need to further research to ensure their long-term safety and reduce potential side effects.¹³⁵ Therefore, chemically modifying the surface of MSNs to improve their targeting and drug release controllability will be an important direction for future research.¹⁶⁴ There is also a need to develop multifunctional MSN systems that can respond to multiple stimuli to achieve more precise drug release and therapeutic effects.¹⁶⁶

Exosomes and Their Biomimetic Nanovesicles

Exosomes are composed of a lipid bilayer membrane enriched with specific membrane proteins. These proteins not only participate in the formation and secretion of exosomes but also mediate their interaction with target cells.¹⁶⁷ The internal cavity of exosomes can carry various bioactive molecules, including proteins, lipids, RNA, and DNA, which play crucial roles in intercellular communication and signal transmission.¹⁶⁸ Exosomes can protect their internal biomolecules from degradation and remain stable in the circulatory system. They possess excellent biocompatibility and low immunogenicity, allowing safe use in vivo, while also having natural targeting ability. They can recognize and bind to target cells through surface-expressed membrane proteins and receptors, thereby achieving precise delivery.¹³⁶

Exosome-based drug delivery or mimetics can enter cells through endocytosis or membrane fusion, releasing their internal biomolecules, thus achieving efficient delivery.^169,170 The natural targeting of exosomes enables them to recognize and bind to specific cell types, such as tumor cells or immune cells, enabling precise therapy.¹⁷¹ Study found that fusing M1 macrophage-derived extracellular vehicles with REV and liposomes loaded with SR780Fe (REV@SR780Fe@Lip) formed REV@SR780Fe@LEV hybrid nanovesicles. Further modification with RS17 peptide for tumor targeting combined photodynamic therapy, ferroptosis, and cGAS-STING pathway activation, thereby enhancing anti-tumor efficacy through synergistic effects. After laser irradiation, REV@SR780Fe@LEV-RS17 showed anti-tumor effects in the 4T1 breast cancer model, including inhibition of lung and liver metastasis and prevention of tumor recurrence.¹²⁰ (As depicted in Figure 6).

Figure 6 The schematic illustration of Exosome nanoparticles (A) Preparation of exosome nanoparticles. (B) TEM images of exosome nanoparticles at pH 7.4 and pH 5.5. (C) Expression of cGAS-STING pathway-related proteins in 4T1 cells after different treatments. (D–F) Release of CRT (D), HMGB1 (E), and ATP (F) from 4T1 cell supernatant after different treatments. (G) 4T1 Tumor growth curves of 4T1 tumor-bearing mice with various treatments. (H–J) Representative FCM (H) and quantification analysis (I and J) of CTLs in tumor. (ns, no significance;***p < 0.001, ****p < 0.0001).120

Due to their biocompatibility, exosomes are easily taken up by cancer cells and can better target siRNA-mediated oncogenic Kras. When exosomes are administered to tumor-bearing mice, the CD47 molecule on their surface reduces their clearance through phagocytosis in the circulation, thereby enhancing the anti-tumor response.¹²¹ Simultaneously, extracellular vehicles have been identified as natural mediators of signal transduction between cancer cells and tumor-resident APCs. Su et al designed a nanoplatform named exoSTING, an innovative engineered extracellular vesicle therapeutic candidate encapsulating a CDN STING agonist. Compared to free CDN, this EV-based delivery system demonstrated significantly enhanced therapeutic potential: efficacy increased by more than 100-fold in preclinical tumor models, while significantly improving tumor retention and reducing systemic cytokine release.^122,172 The amount of naturally extracted exosomes is too low, and purification is time-consuming and costly. Therefore, researchers developed an exosome mimetic (EM) nanocarrier to address these shortcomings. Yawen Guo et al used exosome mimetic nanoparticles to load REV and DOX, named EM@REV@DOX. These drug-loaded nanoparticles can be easily produced in large quantities. EM@REV@DOX showed effective accumulation at the tumor site and was retained there due to EPR and homing targeting effects.¹²³

Exosome nanoparticles although showing significant advantages in biocompatibility, natural targeting, and ability to cross biological barriers, have low yield, making large-scale preparation difficult. The isolation and purification processes are complex and costly, which limits the scalability of their clinical application.¹³⁷ Second, the drug loading efficiency of exosomes is relatively low, especially for large molecules or hydrophobic drugs, requiring further optimization of encapsulation technology to improve drug loading capacity and stability.¹⁷³ Furthermore, exosomes are highly heterogeneous; exosomes from different cell sources may differ in composition and function, which may lead to inconsistencies in delivery.¹⁷⁴ Finally, the metabolism and clearance mechanisms of exosomes in vivo are not yet fully understood, which may affect their safety and effectiveness for long-term use.

The Emerging Role of cGAS-STING Activation by Nanoagonists in Cancer Immunotherapy

The development of OSCC typically progresses from normal epithelium to precancerous lesions eventually evolving into invasive cancer. During this process, genetic mutations may alter the immune microenvironment, inhibiting the function of tumor-infiltrating lymphocytes (TILs), preventing them from clearing precancerous and cancer cells.¹⁷⁵ Specifically, mutations in classic head and neck squamous cell carcinoma driver genes, such as TP53, CDKN2A, and NOTCH1, are associated with the formation of an immunosuppressive tumor microenvironment.^176–179 These mutations may induce the infiltration of regulatory T cells and myeloid-derived suppressor cells, as well as the phenotypic switch of tumor-associated macrophages from M1 to M2 type, thereby inhibiting the function of cytotoxic T lymphocytes.¹⁸⁰ TP53 is the most frequently mutated gene in solid cancers and has a profound impact on multiple hallmarks of cancer. TP53 mutations are common in young adult OSCC, with 45% of tumors showing truncating mutations.¹⁸¹ Mutant p53 not only interferes with the infiltration of myeloid cells and T cells into the tumor microenvironment but also promotes an immunosuppressive state by interacting with TBK1 to drive tumor progression.¹⁸² For example, mutant p53R172H can construct a complex cytokine transcriptome network that inhibits the infiltration of cytotoxic CD8+ T cells while promoting the intratumoral recruitment of regulatory T cells and M2 macrophages.¹⁸³ Furthermore, tumors carrying the p53R172H mutation are infiltrated by numerous CD8+ and CD4+ T cells that express programmed cell death protein 1. These cells showed some responsiveness to immune checkpoint inhibitors and stimulator of interferon genes 1 agonist therapy.¹⁸⁴ These findings reveal the key role of p53 mutation in shaping the tumor immune microenvironment and provide new ideas for the development of related treatment strategies. In addition to genetic mutation‑driven immunosuppression, emerging biomarkers in OSCC can inform prognosis and predict immunotherapy response. A recent study identified cuproptosis‑related lncRNA signatures that correlate with patient prognosis and immunotherapy outcomes in OSCC.¹⁸⁵ Given the mechanistic intersection between cuproptosis and the cGAS‑STING pathway, this finding suggests that STING nanoagonist design should consider multiple tumor metabolic and immune pathways to achieve more precise therapeutic effects.

The cGAS-STING pathway is often in a low-activity state in tumors.¹⁸⁶ Studies have shown that oral cancer cells inhibit the activation of the cGAS-STING pathway through various mechanisms, including reducing cGAS expression, increasing STING protein degradation, or inhibiting downstream signal transduction.^186–188 This dysregulation leads to reduced production of type I interferons in the tumor microenvironment, further weakening anti-tumor immune responses. For example, ARID 1A-regulated DNA repair pathways and interferon-STAT 1-induced TREX 1 expression reduce the level of DNA in tumor cells and limit the type I interferon produced by the cGAS-STING pathway. N-MYC reduces STING oligomerization, USP 35 deubiquitinates STING to limit STING signaling in cancer.^189–191 Simultaneously, inhibiting IL-6 or its downstream JAK2/STAT3 signaling pathway can restore the responsiveness of DU145 cells to STING agonists.¹⁹² In mouse TRAMP-C2 prostate cancer cells, STING activity is crucial for tumor rejection and immune cell infiltration. Although endogenous STING agonists present in TRAMP-C2 cells contribute to tumor rejection, administration of cGAMP can further inhibit tumor growth.⁸² In summary, STING contributes to tumor rejection in tumor cells, but its function is often partially suppressed by the JAK2 and STAT3 pathways. Therefore, restoring the activity of the cGAS-STING pathway may be a key strategy to overcome the immunosuppressive microenvironment of oral cancer. Similarly, sustained activation of the cGAS-STING pathway in cancer leads to chronic inflammation, releasing pro-inflammatory factors such as IL-6 and TNF-α, creating an immunosuppressive microenvironment that weakens anti-tumor immune responses;⁸² furthermore, cytoplasmic DNA accumulation caused by chromosomal instability can chronically activate the cGAS-STING signaling pathway, which in this case promotes tumor growth and metastasis.¹⁹³ Therefore, interventions targeting this pathway in cancer treatment require careful consideration of its dual pro-inflammatory and anti-tumor effects. Recent studies have highlighted that cancer cells exhibit an abnormal accumulation of dsDNA in the cytoplasm, resulting from genomic instability and mitochondrial dysfunction, which in turn activates the cGAS/STING signaling pathway to trigger anti-tumor immune responses. But to evade immune surveillance, cancer cells often inhibit cGAS/STING signaling through epigenetic silencing, gene mutation or deletion, interference by viral oncoproteins and oncogene proteins, and other methods. Furthermore, cancer cells evade immune attack through mechanisms such as loss of antigen presentation, induction of immune checkpoint molecules, recruitment of immunosuppressive cells during the immune editing process. Mitochondrial DNA leakage also prompts cancer cells to selectively inhibit STING expression to avoid STAT1-mediated cytotoxicity.^{7,27,194–196} These mechanisms collectively lead to the suppression of cGAS/STING signals, allowing cancer cells to evade immune surveillance, promote tumor progression, and cause resistance to immunotherapy. Understanding these mechanisms is crucial for developing effective immunotherapy strategies.

Combination Therapy Based on STING Nano-Agonists

Combination therapy based on STING nano-agonists is an important research direction in the field of cancer immunotherapy in recent years. Although monotherapy has achieved certain results in tumor treatment, its efficacy still has limitations and hard to meet clinical needs.⁸ In contrast, multimodal combination therapy shows significant advantages in cancer treatment. Nanotechnology has enhanced the stability, targeting, and controlled release capabilities of STING agonists, addressing issues such as rapid degradation, low delivery efficiency, and systemic toxicity associated with traditional agonists. STING nano-agonists can be combined with various treatment methods. They not only significantly improve treatment effects through synergistic effects but also reduce toxic side effects by lowering drug doses and effectively overcome tumor drug resistance issues.^8,30 This article focuses on typical combination therapy strategies based on cGAS-STING pathway activation, including the combined application of STING nano-agonists with immunotherapy, chemotherapy, and radiotherapy. These synergistic treatment plans provide new ideas and potential solutions for cancer immunotherapy based on cGAS-STING pathway activation.Figure 7 illustrates various combined treatment options.

Figure 7 Enhancing anti-tumor immune response: Mechanism diagram of the combined effect of STING agonists with various treatment regimens.

STING Agonist Combined with Radiotherapy

Radiotherapy is a traditional cancer treatment method that uses high-energy radiation to destroy tumor cell DNA, inhibiting tumor growth by directly killing tumor cells or inducing their apoptosis.^197,198 However, the effect of radiotherapy is not limited to local killing; it can also activate the immune system by releasing tumor antigens and damage-associated molecular patterns, triggering systemic anti-tumor immune responses, a phenomenon known as the “abscopal effect”¹⁹⁹ Nevertheless, when used alone, radiotherapy’s ability to activate the immune system is limited and may be compromised by immunosuppression in the tumor microenvironment.¹⁹⁷ Combining STING agonists with radiotherapy can significantly enhance this immune activation effect. Radiotherapy-induced DNA damage can lead to the accumulation of cyclic dinucleotides in the cytoplasm, thereby activating the STING pathway, further promoting the production of type I interferons and pro-inflammatory factors, enhancing antigen presentation and T cell infiltration.¹⁴ Furthermore, the addition of STING agonists can overcome the immunosuppressive state of the tumor microenvironment, enhance the abscopal effect of radiotherapy, and simultaneously produce synergistic anti-tumor effects on primary and metastatic lesions.²⁰⁰ This combination strategy not only improves the local therapeutic effect of radiotherapy but also inhibits distant metastases through systemic immune activation, providing a more comprehensive solution for cancer treatment.²⁰¹ For example, the high electron density of functionalized hafnium oxide nanoparticles (NBTXR3) allows a high probability of interaction with incoming ionizing radiation and increases energy dose deposition within cancer cells. Due to this physical mode of action, treatment with RT-activated NBTXR3 compared to RT alone increases cancer cell death and better local tumor growth control.²⁰² Simultaneously, Hf ⁴⁺ can successfully activate the cGAS stimulator of STING pathway, promote DC maturation and the production of IFN and other cytokines, thereby further strengthening the RT-induced immune response.⁹⁰ Furthermore, different doses of RT can induce varying degrees of radioimmunotherapy. High-dose radiation (>10 Gy) may lead to immunosuppression, while medium dose (4–10 Gy), although able to alleviate immunosuppression caused by high-dose radiation, is usually insufficient to effectively kill tumor cells. Recently, Jian et al proposed a novel multifunctional nanoplatform RMLF, integrating a Ru (II) complex into folate-functionalized liposomes with BSA-MnO₂ nanoparticles. Orthogonal experiment optimization enhanced radiosensitization by increasing accumulation in cancer cells, increasing ROS, and contributing to the dual enhancement of the cGAS-STING-dependent type I IFN signaling pathway, aiming to overcome the common DAMP deficiency in conventional RT at 4 Gy.¹⁴³

New nanomaterials are developed for radiosensitization through three main methods. First, atoms with high atomic numbers tend to enhance the energy deposition of ionizing radiation, so these elements can be applied for radiosensitization. Second, modulating the tumor microenvironment is also a strategy to improve treatment efficiency. Finally, nanomedicines that normalize blood vessels can accelerate blood flow in the tumor area, thereby alleviating hypoxia and increasing the sensitivity of tumor cells to ionizing irradiation. Liu et al constructed a new nanozyme using MnCO and built it onto dendritic mesoporous silica nanoparticles, with TPP linked to the surface (MDP). MDP can not only stimulate POD-like activity but also CAT-like activity under tumor-mimetic conditions, meaning MDP produces toxic ·OH from H₂O₂ and induces mitochondrial death due to TPP surface modification. Meanwhile, MDP can convert H₂O₂ to O₂, alleviating hypoxia to overcome radioresistance. Ru, as a high Z atom, enhanced the local energy of X-rays. More importantly, results showed that when MDP was applied for radiosensitization, cGAS-STING was upregulated.¹¹⁸ Similarly, Mengling Shen et al collected OMVs and performed biomineralization with MnO₂ to obtain OM@MnO₂-PEG nanoparticles, enhancing tumor radioimmunotherapy by increasing RT-induced ICD and cGAS-STING activation. In the acidic tumor microenvironment, OM@MnO₂-PEG nanoparticles can react with H₂O₂, then producing a large amount of Mn²⁺, O₂, and OM fragments. The alleviated tumor hypoxia improved tumor radiosensitivity, amplifying RT-induced ICD and cGAS-STING activation. Meanwhile, oxygen/OMs promote macrophage polarization to the anti-tumor M1 type, and OM fragments improve the efficiency of tumor antigen presentation by recognizing lipopolysaccharide (LPS) and toll-like receptors (TLR). Notably, the long-term high content of manganese ions in the tumor maintained the activated state of the cGAS-STING pathway. Figure 8 shows the therapeutic effect of the combined treatment of cGAS-STING and radiotherapy.^{77,90,107,118}

Figure 8 Potential of STING nanoparticles in combination therapy with radiotherapy. (A and B) TEM images of STING nanoparticles. (C) Image of cancer cell survival obtained by incubating with different concentrations of STING nanoparticles for 24 hours, then irradiating with different doses of X-rays. (D) Representative images of colony cluster staining after receiving various treatments. (E) Survival rate of cancer cells in different treatment groups. (F)Viability of cancer cells after treatment with different treatment groups. (G) Tumor weight in mice. (H) Image of tumors collected from mice after treatment with various drugs. (**p < 0.01,***p < 0.001, ****p < 0.0001).77,90,107,118

STING Agonist Combined with Chemotherapy

Chemotherapy is a traditional cancer treatment method that uses chemical drugs to kill or inhibit the growth of cancer cells. These drugs work by interfering with DNA replication, cell division, or other key metabolic processes of cancer cells. However, the primary limitation of chemotherapy is its lack of specificity. It not only eliminates tumor cells but also damages healthy tissues, leading to severe side effects such as immunosuppression, nausea, and hair loss. Moreover, tumor cells can develop resistance to chemotherapeutic agents, further compromising treatment efficacy.²⁰³

In recent years, combination chemotherapy strategies based on STING nano-agonists have offered new approaches to overcoming these limitations. STING agonists activate the cGAS-STING pathway to enhance anti-tumor immune responses. The application of nanotechnology further improves the stability and targeting of STING agonists, enabling their precise delivery to the tumor microenvironment.⁸⁴ When combined with chemotherapy, chemotherapeutic drugs induce immunogenic cell death of tumor cells, releasing tumor antigens, while STING agonists activate antigen-presenting cells and T cells, enhancing systemic immune responses. This synergistic effect not only improves the therapeutic effect of chemotherapy but also reduces side effects by lowering the dose of chemotherapeutic drugs and overcomes tumor drug resistance.^204,205 Lewicky et al developed a multi-target mannosylated cationic liposome immunomodulatory system containing low-dose chemotherapeutic cytarabine (Ara-C). They demonstrated that embedding non-cytotoxic doses of Ara-C in DS enhanced its ability to induce DNA double-strand breaks in human ovarian and colorectal cancer cell lines and various immune cells. They also proved that Ara-C/DS-induced DNA damage translates into cGAS-STING axis activation, highlighting the broad immunotherapeutic potential of Ara-C/DS through enhanced tumor-directed inflammatory responses.⁷⁶

Another recent study on platinum drugs is that Xiang et al designed composite nanoparticles (NP-Pt-IDOi) from a ROS-sensitive amphiphilic polymer with a thiol-ketone bond in the backbone to encapsulate a Pt (IV) prodrug (Pt (IV)-C12) and an indoleamine-(2,3)-dioxygenase (IDO) inhibitor (IDOi, NLG919). Once NP-Pt-IDOi enters cancer cells, the polymeric nanoparticles dissociate due to intracellular ROS and release Pt (IV)-C12 and NLG919. Pt (IV)-C12 induces DNA damage and activates the cGAS-STING pathway, increasing the infiltration of CD8+ T cells in the tumor microenvironment. Furthermore, NLG919 inhibits tryptophan metabolism and enhances CD8+ T cell activity, ultimately activating anti-tumor immunity and enhancing the anti-tumor effect of platinum drugs.⁸⁵

STING Agonist Combined with Phototherapy

Phototherapy is a non-invasive method that uses light energy for disease treatment, widely used in cancer treatment. Its principle is that photosensitizers absorb light of specific wavelengths, producing photodynamic effects (PDT) or photothermal effects (PTT), thereby inducing tumor cell death.²⁰⁶ The photodynamic effect directly kills tumor cells by generating ROS, while the photothermal effect destroys tumor tissue through local heating.²⁰⁷ The advantage of phototherapy lies in its precision and controllability, enabling selective action on the tumor site and reducing damage to normal tissues.²⁰⁸ The limitation of phototherapy is its limited immune activation ability and may be affected by immunosuppression in the tumor microenvironment.²⁰⁹ Combining STING agonists with phototherapy can significantly enhance the treatment effect. Phototherapy-induced tumor cell death releases tumor antigens and damage-associated molecular patterns (DAMPs), activating the immune system, while STING agonists, via STING pathway activation, further potentiate the immune effects of phototherapy.^27,210

To synergistically utilize the photothermal effect and immune activation, researchers have designed a manganese-based composite nanomaterial. Through a single treatment, it can simultaneously achieve local thermal killing, alleviate tumor immune suppression, and systematically activate anti-tumor immunity. Zheng et al constructed Mn-rich photonic nanomedicine (MnPB-MnO₂). By utilizing manganese-rich photonic nanomedicine with ideal biocompatibility, they effectively activated the cGAS-STING pathway with sufficient Mn²⁺, combined with abundant TAAs derived from damaged cancer cells due to the dual blow of hyperthermia and ROS, synergistically enhancing innate and adaptive anti-tumor immunity, achieving enhanced local photothermal/immunotherapy effects and triggering systemic immune therapy effects.¹⁰⁸ Recently, the AMOPs (gold nanoparticles-Au NPs/manganese dioxide-MnO₂ composite) developed by Xian An’s team revealed the synergistic anti-tumor mechanism of STING agonists and PTT. In the TME, AMOPs catalyze the decomposition of H₂O₂ into O₂, alleviating hypoxia to enhance cytotoxic T lymphocyte (CTL) function. Meanwhile, the high concentration of GSH in tumor cells triggers the PTT effect of AMOPs, inducing ICD and promoting CTL infiltration. Furthermore, Mn²⁺ released from the decomposition of MnO₂ can activate the STING pathway, further enhancing the immune response. This combined effect of STING agonist and PTT not only inhibits primary tumor growth but also establishes immune memory, preventing recurrence and metastasis.¹⁰³ These studies demonstrate that integrating STING agonists into photothermal nanodevices can transform local physical ablation into a combined therapy that not only directly eliminates the lesion but also remodels the tumor immune microenvironment and stimulates a systemic immune response, thereby expanding the application prospects of phototherapy in immunotherapy.

Secondly, in terms of PDT, a new generation of nanomaterials with organelle-level precision has important prospects in maximizing the efficacy of targeted tumor therapy. Hao Tian ‘s team reported a novel amphiphilic phenolic polymer (PF) for mitochondria-targeted PDT, which can trigger excessive mtDNA damage through the synergistic effect of oxidative stress and furan-mediated DNA cross-linking. The phenolic units on PF can further self-assemble with Mn²⁺ through metal-phenolic coordination to form metal-phenolic nanomaterials (PFM). It emphasized that PFM promotes cGAS-STING-dependent immunity at the organelle level, thus having effective anti-tumor efficacy.⁹⁷

Furthermore, the MOF-based nanoagonist (DZ@A7) researched and developed by Xun Guo et al achieves tumor-specific activation of the STING pathway through NIR light-triggered decomposition. Under NIR irradiation, DZ@A7 generates mitochondria-targeting ROS, enhancing the tumor-killing effect of PDT, while consuming GSH to amplify oxidative damage. Additionally, NIR-triggered STING activation synergizes with PDT, significantly enhancing anti-tumor immunity, providing a new strategy for the combination of STING agonists and PDT.¹⁰⁵

Recently, photothermal ablation (PTA) has garnered widespread attention due to its ability to induce local thermal damage through light absorption by suitable agents. The Xia team reported an intelligent glutathione (GSH)-responsive photothermal nanosystem composed of Prussian blue (PB) nanoparticles supported by Mn (III) to generate a synchronous strategy to enhance the immune response treatment of incomplete photothermal ablation. This nanosystem ablates tumors through the photothermal effect of PB under 808 nm near-infrared laser irradiation. Then the exposed Mn (III) consumes GSH present in the tumor tissue. The interaction between Mn (III) and GSH leads to the release of Mn (II). Since the formation of cytoplasmic DNA was observed during photothermal ablation therapy, the synchronous release of Mn (II) is expected to further increase the sensitivity of cGAS to double-stranded DNA (dsDNA), which should promote the activation of the cGAS-STING pathway and remodel the tumor immune microenvironment to improve anti-tumor efficiency.¹⁰² Figure 9 shows the therapeutic effect of the combination of cGAS-STING and various phototherapies.^102,108,109

Figure 9 Potential of STING nanoparticles in combination therapy with phototherapy. (A) Schematic diagram of STING nanoparticle synthesis and its TEM image. (B) Flow cytometry analysis of apoptosis levels in cancer cells after different treatments. (C) Infrared thermal images of tumor models after different treatments. (D) Photographic images of mouse tumors. (E) Relative tumor growth curves of various treatment groups. (F) Temperature profiles of PTA tumor models.102,108,109

Combination Therapy of STING Agonists with Other Immunotherapies

Combination therapy based on STING nano-agonists with other immunotherapies is an important research direction in the field of cancer treatment in recent years. Other immunotherapies include immune checkpoint inhibitors (ICI), ICD inducers, and PD-L1 inhibitors. Immune checkpoint inhibitors restore the anti-tumor activity of T cells by blocking inhibitory signals between tumor cells and T cells, thereby enhancing the attack capability of the immune system.²¹⁰ The efficacy of ICI depends on pre-existing T cell infiltration in the tumor microenvironment and has a limited effect on “cold tumors”²¹¹ ICD inducers activate dendritic cells and promote T cell-mediated immune responses by inducing tumor cells to release DAMPs and tumor antigens.²¹² PD-L1 inhibitors terminated the inhibition of T cells by blocking the binding of PD-L1 on the surface of tumor cells to PD-1 on T cells, enhancing their ability to kill tumors.²¹³

STING nano-agonists significantly enhance the effects of these immunotherapies by activating the cGAS-STING pathway and inducing the production of type I interferons and pro-inflammatory factors. For example, ICI circumvent inhibitory checkpoint molecules on tumor cells, thereby enhancing T cell reactivity and preventing immune exhaustion, thus restoring immune surveillance. When STING agonists are combined with ICI, they can increase T cell infiltration in the tumor microenvironment, converting “cold tumors” into “hot tumors”, thereby improving the efficacy of ICI. To fully utilize the potential of ICI therapy, it is crucial to transform “cold” tumors into a more immunogenic and pro-inflammatory phenotype.³⁶ This transformation can restore anti-tumor immunity, thereby improving the effectiveness of treatment. A particularly feasible method to achieve this goal is to enhance the activity of the cGAS-STING pathway. This pathway is a crucial component of the innate immune system, playing a vital role in anti-viral defense and anti-tumor responses. Recent studies have shown that the STING agonist SR-717 delivered based on an albumin nanocarrier (SH-NPs) can efficiently activate the STING pathway and reverse the immunosuppressive state of the TME. SH-NPs not only enhance T cell anti-tumor immunity but also significantly improve the efficacy of ICI, confirming the synergistic effect of STING agonists and ICI.²¹⁴

Furthermore, as a special type of cell death, the immune response induced by ICD leads to dendritic cell maturation and activation of specific T cells, highlighting its potential as a target for anticancer therapy. The combination of STING agonists and ICD inducers can further enhance the release and presentation of tumor antigens, activating stronger anti-tumor immune responses.²¹⁵ Recent studies have shown that nanoparticles (EM@REV@DOX) loaded with the STING agonist and doxorubicin can activate anti-tumor immunity through a dual mechanism. On the one hand, DOX induces ICD, releasing tumor antigens; on the other hand, REV activates the cGAS-STING pathway, promoting DC maturation and CTL infiltration. This synergistic effect of STING agonist and ICD significantly enhanced the immune response. Combined with PD-L1 blockade, it could further inhibit tumor growth.¹²³ The research of Tianchuan Zhu et al found that the combination of the STING agonist cGAMP and PD-L1 inhibitor produced a synergistic anti-tumor effect. After co-delivery of cGAMP and anti-PD-L1 antibody (aPD-L1 NVs@cGAMP) via nanovesicles, STING pathway activation promoted IFN-β secretion and T cell infiltration, while PD-L1 blockade prevented T cell exhaustion. This combination strategy significantly enhanced the therapeutic effect of CAR-T cells on solid tumors by reshaping the tumor immune microenvironment.¹¹⁹ These combination strategies not only significantly improve treatment effects through synergy but also reduce side effects by lowering drug doses and overcoming tumor drug resistance, providing new ideas and potential solutions for cancer immunotherapy. Figure 10 shows the therapeutic potential of the combination of cGAS-STING and various immunotherapies.^123,216

Figure 10 Potential of STING nanoparticles in combination therapy with other immunotherapies. (A) SEM image of STING nanoparticles. (B and C) Release of HMGB1 and ATP from LLC cells after different treatments, indicating the effect of STING nanoparticles in achieving ICD. (D) Cytokine levels of TNF-α (i), and IFN-β (ii) in DCs after treatments with different formulations. (E) Representative corresponding quantification of CRT release in cells after different treatments. (F–K) Tumor pictures, average tumor growth curves, and survival curves of CT26 tumor-bearing mice after treatment with STING nanoparticles. (** p < 0.01,**** p < 0.0001).123,216

STING Agonists are Used in Combination with Various Treatment Methods

In some complex clinical scenarios, relying solely on one or two treatment strategies based on the cGAS-STING pathway may be difficult to fully address tumor heterogeneity and individualized patient needs. To this end, researchers have begun to explore integrating multiple treatment methods into combination platforms based on STING nano-agonists to achieve more comprehensive anti-tumor effects. In addition to the combinations discussed in Combination Therapy of STING Agonists with Other Immunotherapies, STING nano-agonists can be further integrated with multiple modalities simultaneously, such as chemotherapy, radiotherapy, and phototherapy.

Recently, it was found that using polyethylene glycol grafted poly copolymer (mPEG-PLGA, PP) as a biodegradable and biosafe micelle carrier, loading vadimezan (DMXAA), obtained PLGA-PEG/DMXAA (PPD) for multiple synergistic therapies of cancer and its metastasis/recurrence. After intravenous injection, PPD can effectively accumulate at the tumor site and trigger tumor-specific thrombosis. Furthermore, blood clots in the tumor can convert near-infrared light into heat and temporarily provide oxygen to tumor tissue to enhance PTT/RT. Besides PTT/RT, DMXAA-induced tumor vascular damage leads to starvation therapy for cancer.⁹⁵ These multimodal combination strategies significantly improve treatment efficacy through synergistic effects while reducing drug doses and side effects, providing more flexible and efficient solutions for cancer treatment.

The strategy of combining STING nano-agonists with multiple treatment methods, although showing great potential in cancer treatment, still faces some challenges and limitations. First, the complexity of multifunctional combination nano-systems may hinder their large-scale production and clinical application. Complex preparation processes and high costs limit their feasibility in industrial production. Second, the synergistic mechanism of multiple treatment methods is not yet fully clear, making it difficult to accurately evaluate the specific contribution of each method in combination therapy, which brings difficulties to optimizing treatment plans. Furthermore, as the number of therapeutic drugs and combination methods increases, the risk of potential toxic side effects also rises, which may adversely affect patient tolerance. Therefore, when designing multi-mode treatment systems based on STING nano-agonists, it is necessary to comprehensively consider the drug dose, delivery efficiency, and biological safety, especially for complex systems involving multiple therapies.

Challenges and Prospects

Although nano-drug delivery systems have made significant progress, ensuring precise drug delivery to the tumor site without off-target effects remains a complex issue, such as the targeted delivery of STING agonists and maintaining their stability in the tumor microenvironment.⁹ The degradation of STING agonists in the blood and their limited penetration into tumor tissue can significantly reduce treatment efficacy. Furthermore, the immunosuppressive characteristics of the tumor microenvironment pose a major obstacle, as tumor cells often evade immune detection through mechanisms such as downregulating STING expression or upregulating immune checkpoint molecules. Overcoming these immune escape strategies is crucial for enhancing the therapeutic potential of STING agonists. Although nano-drug delivery systems improve the delivery and stability of STING agonists, potential toxicity and side effects remain concerns. The long-term impact of nanoparticles on normal tissues and the immune system requires in-depth study. The systemic release of cytokines caused by STING activation may lead to adverse reactions, such as cytokine release syndrome.^217–219 The complexity of combining STING agonists with other therapies adds challenges to the treatment regimen. The synergistic effects of these combinations need careful balancing to avoid overactivation of the immune system or excessive toxicity. Optimizing dosing regimens and understanding the interactions between different treatment modes are crucial.²²⁰ Finally, the production of nano-drug delivery systems for STING agonists involves complex technologies and materials, which are costly and difficult to scale up. Developing cost-effective and scalable manufacturing processes is necessary to make these therapies accessible to a wider patient population.¹²⁹

Several potential directions can address these challenges and enhance the efficacy of STING-based therapies. Future research should focus on developing next-generation nano-drug delivery systems with enhanced targeting capabilities and stimulus-responsive characteristics. For example, smart nanoparticles that release STING agonists only in the presence of specific tumor markers or microenvironment signals can improve precision and reduce off-target effects.²²¹ Strategies to reprogram the tumor microenvironment and enhance immune cell infiltration are also crucial. Combining STING agonists with drugs that modulate the tumor microenvironment, such as inhibitors of immune checkpoint molecules or cytokines that promote dendritic cell maturation, can enhance the overall immune response. Additionally, personalized approaches based on the patient’s immune signature can optimize treatment outcomes. Exploring novel combinations of STING agonists with emerging therapies, such as oncolytic viruses or adoptive cell therapy, may open new avenues for cancer treatment. These combinations can leverage the advantages of each treatment modality, creating more robust and durable anti-tumor immune responses.²²² Furthermore, combining STING agonists with precision medicine approaches, such as targeting specific genetic mutations, can further enhance treatment efficacy. Identifying biomarkers that predict response to STING agonists can enable more personalized and effective treatment strategies.²²³ Understanding the molecular and immunological characteristics of tumors that respond well to STING activation can guide patient selection and improve clinical outcomes. Efforts should also be made to streamline the clinical translation of STING therapies. This includes conducting large-scale clinical trials to determine safety and efficacy, as well as developing cost-effective production methods.⁴²

Future research can explore the development of smart nanoparticles capable of releasing STING agonists based on specific signals in the TME. Such intelligent delivery systems can further improve treatment precision and reduce damage to normal tissues.²²⁴ Furthermore, besides using STING agonists, future research can explore how to reprogram the tumor microenvironment through gene editing or epigenetic regulation to shift it from an immunosuppressive state to an immune-activated state. This strategy can be used in combination with STING agonists to further potently boost antitumor immunity.²²⁵ Combining multimodal imaging techniques with STING agonist therapy can enable real-time monitoring of tumors and evaluation of treatment effects. This technology can help doctors adjust treatment plans based on dynamic changes in tumors, improving the individualization and precision of treatment. Future research can also explore combining STING agonists with tumor antigens to develop nanovaccines. Such vaccines can not only activate the STING pathway but also induce immune responses against specific tumor antigens, thereby enhancing anti-tumor effects.²²⁶ Finally, utilizing artificial intelligence and big data analytics can help better understand the differences in the efficacy of STING agonists among different patients and optimize treatment plans. By analyzing patient genomic, immune, and clinical data, AI can help predict treatment responses and develop personalized treatment strategies.²²⁷

Beyond the classical cGAS-STING signaling cascade, recent studies have revealed non-canonical functions of pathway components that warrant attention in future cancer immunotherapy.²²⁸ For instance, the second messenger cGAMP not only activates STING to induce type I interferon responses but also directly interacts with Rab18, promoting cell migration and tumor metastasis.²²⁹ This finding suggests that STING nanoagonist therapy may carry a potential risk of pro‑metastatic effects, or conversely, this mechanism could be harnessed to enhance immune cell chemotaxis toward tumor sites.⁸⁴ Furthermore, cGAS and STING each have independent functions: cGAS directly regulates DNA damage repair and cellular senescence, whereas STING induces autophagy, reprograms metabolism, and modulates apoptosis.^230–232 Activation or inhibition of these non‑canonical functions could produce dramatically different therapeutic outcomes depending on tumor type and microenvironment context. Therefore, future design of nanodelivery systems should consider selective modulation of these non‑canonical pathways to achieve more precise and safer cancer immunotherapy.

Conclusion

In summary, nanocarrier-based delivery systems for STING agonists show great promise in cancer immunotherapy. Lipid, polymeric, metallic, mesoporous silica, and exosomal nanoplatforms each have their own advantages and limitations, and should be selected based on therapeutic goals. Combining nanoagonists with radiotherapy, chemotherapy, phototherapy, and immune checkpoint inhibitors produces synergistic effects, improving efficacy and reducing toxicity. Although challenges such as protein corona formation, scalable manufacturing, and long-term safety remain, smart responsive nanomaterials, biomimetic designs, and personalized strategies position STING nanoagonists as key components of next-generation cancer immunotherapy.