Stimulator Of Interferon Genes Pathway Research Articles

TMOD-32. MURINE MODELLING OF THE STING PATHWAY IN GLIOMAS

Abstract The stimulator of interferon genes (STING) pathway is a critical component of innate antitumor immunity through the recognition of pathogenic cytosolic DNA and stimulating the production of type 1 interferons and pro-inflammatory cytokines. We have previously shown that STING signaling is silenced in the neoplastic compartment of the GBM tumor microenvironment, but remains intact in vascular and immune cells. In human patient derived cell lines, such silencing appears to be mediated by hypermethylation of a region of the STING promoter and can be reversed by treatment with both the DNA methyltransferase (DNMT) inhibitor Decitabine and DNMT1-selective inhibitor GSK-3685032. These results suggest that neoplastic cell STING promoter methylation represents a therapeutic vulnerability that can be exploited by epigenetic therapies to inflame the glioma tumor microenvironment. Murine models are critical tools for exploring the translational implications of STING silencing in vivo. Distinct mouse models have been developed to optimally represent specific aspects of human glioma biology. Here we characterize the STING pathway in commonly used syngeneic murine glioma models, including CT2A, GL261, SB28, and SMA560. We show that the expression of STING pathway components varies significantly across these lines. Importantly, unlike in humans, murine STING (mSTING) expression is not suppressed by promoter methylation and does not respond to decitabine treatment. Additionally, the mSTING protein is expressed in neoplastic cells in vivo. These results demonstrate a fundamental difference in epigenetic regulation of STING between human and murine glioma cells, and suggest that murine modeling of STING epigenetics requires the use of patient derived cell lines implanted in immunodeficient mice. Meanwhile, immune competent syngeneic models are appropriate for exploring the tumor immune microenvironment but would require non-epigenetic approaches (e.g. genetic knock-outs/knock-ins) for modulating STING expression. Humanized mice represent a promising emerging approach for faithfully recapitulating both epigenetic control and immune environment of human gliomas.

IMMU-54. THERAPEUTIC TARGETING OF STING IN MENINGIOMAS

Abstract Up to one-quarter of meningiomas recur within five years of resection; however, there are currently no established adjuvant therapies for lesions that are intractable to surgery and radiation. To identify novel treatment approaches, scRNA-sequencing datasets were reanalyzed from thirteen meningiomas and nine adjacent dura samples including >30,000 immune cells from varying WHO grades and molecular subtypes. In contrast to gliomas, immune-inducing STING (stimulator of interferon genes) was expressed within the meningioma tumor cells, consistent with DNA methylation profiling that showed hypomethylation of the STING promotor in 93% of cases (267 of 288 meningiomas; beta < 0.2). Meningiomas in the immune-enriched subgroup additionally exhibited significant hypomethylation in the 3’ UTR of this gene (p = 1.9 x 10-9). Using sequential multiplex immune fluorescence, STING expression was confirmed in neoplastic, myeloid, and endothelial cells within all grades of meningiomas, but not in adjacent dura and brain. Downstream STING pathway activation markers such as p-IRF3 were partially expressed, suggesting that further activation of the STING pathway may offer therapeutic benefits. Ex vivo single-cell suspensions of resected human meningiomas treated with the STING agonist 8803 induced 25-45% growth inhibition in 7/8 cases within 72 hours (p < 0.001; two-way ANOVA). There was no growth inhibition of the meningioma cell lines IOMM-LEE and CH157 treated with 8803, which lack immune cells and contain only clonal neoplastic cells. However, when the IOMM-LEE meningioma cells were implanted in vivo, a single dose of 8803 induced a >50% reduction in tumor volume relative to the vehicle control injection at multiple time points (p < 0.001; two-way ANOVA) indicating that the immune system is an essential component of STING efficacy in these tumors. Our results reveal widespread expression of STING in neoplastic and myeloid populations in meningiomas and clarify a new treatment indication for use of the STING agonist 8803.

Tandem‐Controlled Dynamic DNA Assembly Enables Temporally‐Selective Orthogonal Regulation of cGAS–STING Stimulation

Despite advances in the controlled reconfiguration of DNA structures for biological applications, the dearth of strategies that allow for orthogonal regulation of immune pathways remains a challenge. Here, we report for the first time an endogenous and exogenous tandem‐regulated DNA assembly strategy that enables orthogonally controlled stimulation of the cyclic GMP‐AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway. A DNA motif containing two palindromic sequences is engineered with an abasic site (AP)‐connected blocking sequence to inhibit its self‐assembly function, while apurinic/apyrimidinic endonuclease 1 (APE1)‐triggered enzymatic cleavage of the AP site enables the reconfiguration and self‐assembly of DNA motif into long double‐stranded structures, thus realizing allosteric activation of the catalytic activity of cGAS to produce 2’3’‐cyclic‐GMP‐AMP for STING stimulation. Importantly, we demonstrate that APE1‐regulated DNA assembly allows for cell‐selective activation of cGAS–STING signaling. Furthermore, by re‐engineering the DNA motif with a photocleavable group, enzyme‐triggered DNA assembly allows the cGAS–STING stimulation to operate (switched "ON''), whereas light‐mediated fragmentation of the double‐stranded DNA enables termination of such stimulation (switched "OFF"), thereby achieving orthogonal control over immune regulation. This work highlights an endogenous and exogenous tandem regulated strategy to modulate the cGAS–STING pathway in an orthogonally controlled manner.

IMMU-19. PRECLINICAL THERAPEUTIC ACTIVITY AND PET IMAGING OF STING AGONIST 8803 IN GLIOBLASTOMA

Abstract STING (stimulator of interferon genes) activation triggers interferon (IFN) release within the tumor microenvironment from myeloid cells and other cell types, inducing proinflammatory anti-tumor immune responses. The small molecule STING agonist, 8803, elicits long-term survival in 56% (QPP4; p=0.0003) to 100% (QPP8; p<0.0001) of mice with orthotopically implanted immune checkpoint-resistant glioblastoma models after 2-3 doses. In humanized mice, in which glioblastoma-cell STING is epigenetically silenced, 8803 therapeutic activity is maintained. The combination therapy of 8803 with anti-PD-1 relatively further enhances survival in immune checkpoint-resistant models. Ex vivo flow cytometry and proteomic sequential multiplex profiling during the therapeutic window demonstrate global immunological reprogramming, specific tumor-antigen immune responses, increased tumor immune effector trafficking, and release of IFN. It has been shown that IFN signaling augments intracellular nucleotide metabolism and increases [18F]-FLT uptake in pancreatic cancer. We evaluated the longitudinal [18F]-FLT uptake in CT-2A-bearing mice using MRI/PET/CT at days 0, 2, and 4 after intratumoral 8803 delivery. Brain images were acquired before and after [18F]-FLT tracer and 8803 administrations. The CT was used for PET attenuation/correction, and the MRI was used for tumor segmentation. Regional analysis of PET-derived [18F]-FLT SUV maps used advanced image processing approaches as a function of time to enhance the voxel-by-voxel interpretation of the acquired images. [18F]-FLT uptake increased from baseline in all mice treated with 8803 compared to control mice with a peak at 48-96 hours. Concordant sequential multiplex immunofluorescence demonstrated that the STING expression was prominent along the tumor vasculature, myeloid, and tumor cells. p-IRF-3 expression, reflective of STING pathway activation, showed a diffuse pattern after treatment. Based on the preclinical data, PET imaging at 48-96 hours post-treatment represents the appropriate imaging modality and timepoint to maximize the ability to detect STING-dependent changes for a therapeutic strategy that reprograms the glioblastoma microenvironment and improves survival across multiple preclinical models of glioblastoma.

The cGAS-STING mediated crosstalk between innate immunity and autophagy in leishmaniasis using mathematical modeling: Uncovering new therapeutic avenues

The present paper deals with the investigation into the cGAS-STING pathway, focusing on the signaling of interferons through mathematical modeling and identifying a significant positive feedback loop regulated by STING for activation of type 1 interferons (IFN-1). Cyclic GMP-AMP synthase (cGAS) is responsible for detecting cytosolic DNA and initiating the STING (stimulator of interferon genes) pathway, which in turn causes the synthesis of pro-inflammatory cytokines and type I interferons. In addition to being crucial for pathogen identification, this route interacts with autophagy, a cellular mechanism that is necessary for immunological homeostasis and pathogen removal. In the context of Leishmania infection, the cGAS-STING signaling axis has come to light as a critical mediator of the crosstalk between innate immunity and autophagy. Further, the protein-protein interaction studies underscored the significance of two distinct domains in mediating interactions with IRF3 and LC3. Importantly, our findings suggest the possibility of manipulating STING concomitantly to regulate IRF3 and LC3 independently. This study remarkably advances our understanding of STING's multifaceted roles, particularly in regulating IFN-1 and autophagy, highlighting its pivotal role as a cross-talk point in leishmaniasis.

Enhanced Tumor Immunotherapy by Triple Amplification Effects of Nanomedicine on the STING Signaling Pathway in Dendritic Cells.

Insufficient activation of stimulator of interferon genes (STING) signaling pathway in tumor-associated dendritic cells limits the efficiency of tumor immunotherapy. Herein, the "three-in-one" IAHA-LaP/siPTPN6 NPs containing lanthanum ions (La3+), cGAMP, and PTPN6 siRNA are developed for triple amplification of the STING pathway. In vitro results demonstrate that La3+ significantly promotes cGAMP-mediated activation of the STING pathway by enhancing the phosphorylation of STING, TBK1, IRF3, and NF-κB p65. Moreover, the IAHA-LaP/siPTPN6 NPs further significantly enhance the phosphorylation of STING and NF-κB p65 and augment K63-linked ubiquitination of STING protein via siPTPN6-mediated downregulation of SHP-1 protein. Furthermore, NPs improve the secretion of IFNβ (2.4-fold), IL-6 (1.5-fold), and TNF-α (1.4-fold), thereby promoting DCs maturation compared to the mixture of La3+ and cGAMP. In vivo results show that the IAHA-LaP/siPTPN6 NPs remarkably inhibit primary tumor growth by increasing the percentage of mature DCs in tumor-draining lymph nodes, polarizing M2/M1 phenotype in TME, and promoting the infiltration of CD8+T cells into tumors. Moreover, these NPs dramatically prevent the growth of distal tumor by inducing systemic anti-tumor immunity and generating a long-term anti-tumor memory for protection against tumor recurrence in mice bearing bilateral B16F10. These IAHA-LaP/siPTPN6 NPs may offer a promising platform for robust anti-tumor immune responses.

Mesoporous Microneedles Enabled Localized Controllable Delivery of Stimulator of Interferon Gene Agonist Nanoexosomes for FLASH Radioimmunotherapy against Breast Cancer.

The immunosuppressive nature of the tumor microenvironment (TME) contributes to radioresistance, thereby impairing the effectiveness of radiotherapy as a therapeutic intervention. Activation through the stimulator of interferon genes (STING) pathway shows potential in modulating immunogenicity. However, the therapeutic efficacy of STING agonists might be restricted by off-target effects and potential cytotoxicity. In this work, nanoexosomes (EXOs) loaded within porous microneedles were employed for precise delivery of the STING agonist MSA-2 (MEM) to the tumor site. Leveraging the enhanced tumor penetration enabled by microneedles, EXOs can be continually released and accumulate within deep residual tumors. Once internalized, these EXOs release the encapsulated MSA-2, facilitating the activation of the STING pathway upon exposure to ultrahigh dose-rate (FLASH) irradiation. This strategy elevates the type I interferon level, promotes dendric cell maturation, and modulates the immunosuppressive TME, showing efficient antitumor efficacy in both primary/metastatic tumors. Furthermore, the induction of a potent immune response effectively prevented tumor recurrence. The combination of EXO-loaded microneedles with FLASH radiotherapy resulted in minimal systemic side effects, attributed to precise drug delivery and radioprotection conferred by FLASH. Altogether, the strategic design of EXO-loaded microneedles holds promise for enhancing MSA-2 delivery, thereby mitigating the radioresistant tumor microenvironment through STING cascade activation-mediated immunotherapy, consequently optimizing the outcomes of FLASH radiotherapy.

Stimulator of interferon gene facilitates recruitment of effector CD8 T cells that drive neurofibromatosis type 1 nerve tumor initiation and maintenance.

Plexiform neurofibromas (PNFs) are benign nerve tumors driven by loss of the NF1 tumor suppressor in Schwann cells. PNFs are rich in immune cells, but whether immune cells are necessary for tumorigenesis is unknown. We show that inhibition of stimulator of interferon gene (STING) reduces plasma CXCL10, tumor T cell and dendritic cell (DC) recruitment, and tumor formation. Further, mice lacking XCR-1+ DCs showed reduced tumor-infiltrating T cells and PNF tumors. Antigen-presenting cells from tumor-bearing mice promoted CD8+ T cell proliferation in vitro, and PNF T cells expressed high levels of CCL5, implicating T cell activation. Notably, tumors and nerve-associated macrophages were absent in Rag1-/-; Nf1f/f; DhhCre mice and adoptive transfer of CD8+ T cells from tumor-bearing mice restored PNF initiation. In this setting, PNF shrunk upon subsequent T cell removal. Thus, STING pathway activation contributes to CD8+ T cell-dependent inflammatory responses required for PNF initiation and maintenance.

Robust and Sustained STING Pathway Activation via Hydrogel-Based In Situ Vaccination for Cancer Immunotherapy.

The stimulator of interferon genes (STING) pathway is crucial for tumor immunity, leading to the exploration of STING agonists as potential immunotherapy adjuvants. However, their clinical application faces obstacles including poor pharmacokinetics, transient activation, and an immunosuppressive tumor microenvironment (TME). Addressing these limitations, our study aims to develop an injectable silk fibroin hydrogel-based in situ vaccine. It incorporates a nanoscale STING agonist, an immunogenic cell death (ICD) inducer, and an immunomodulator to ensure their controlled and sustained release. cGAMP nanoparticles (cGAMPnps) with a core-shell structure ensure optimal delivery of cGAMP to dendritic cells (DCs), thereby activating the STING pathway and fostering DC maturation. ICD-associated damage-associated molecular patterns amplify and prolong STING activation via enhanced type I IFN and other inflammatory pathways, along with delayed degradation of cGAMP and STING. Furthermore, the STING-driven vascular normalization by cGAMPnps and ICD, in conjunction with immunomodulators like antiprogrammed cell death protein 1 antibody (anti-PD-1 Ab) or OX40 ligand (OX40L), effectively remodels the immunosuppressive TME. This in situ gel vaccine, when used independently or with surgery as neoadjuvant/adjuvant immunotherapy, enhances DC and CD8+ T-cell activation, suppressing tumor progression and recurrence across various immunologically cold tumor models. It revolutionizes the application of STING agonists in cancer immunotherapy, offering substantial promise for improving outcomes across a broad spectrum of malignancies.

Targeting STING signaling for the optimal cancer immunotherapy.

Despite the transformative impact of anti-PD-1/PD-L1 therapies, challenges such as low response rates persist. The stimulator of interferon genes (STING) pathway, a crucial element of innate immunity, emerges as a strategic target to overcome these limitations. Understanding its multifaceted functions in cancer, including antigen presentation and response to DNA damage, provides valuable insights. STING agonists, categorized into cyclic dinucleotides (CDNs) and non-CDNs, exhibit promising safety and efficacy profiles. Innovative delivery systems, including antibody-drug conjugates, nanocarriers, and exosome-based therapies, address challenges associated with systemic administration and enhance targeted tumor delivery. Personalized vaccines, such as DT-Exo-STING, showcase the adaptability of STING agonists for individualized treatment. These advancements not only offer new prospects for combination therapies but also pave the way for overcoming resistance mechanisms. This review focuses on the potential of targeting STING pathway to enhance cancer immunotherapy. The integration of STING agonists into cancer immunotherapy holds promise for more effective, personalized, and successful approaches against malignancies, presenting a beacon of hope for the future of cancer treatment.

Mobilizing STING Pathway via a Cationic Liposome to Enhance Doxorubicin‐Induced Antitumor Immunity

AbstractThe efficacy of anthracycline, such as doxorubicin (DOX), is facilitated by cancer cell‐intrinsic type I interferon (IFN‐I) signaling through the induction of immune responses. However, weak and chronic IFN‐I responses from rounds of chemotherapy lead to resistance against DNA damage and acquired resistance to the therapy. An exogenous supply of IFN‐I can improve the chemotherapeutic responses. Herein, a library of cationic liposomes is developed for the optimization of 1, 2‐dioleoyl‐3‐trimethylammonium‐propane (DOTAP) proportions to enhance the lysosome escape and tumor distribution of the stimulator of interferon genes (STING) agonist 2′,3′‐cyclic guanosine monophosphate‐adenosine monophosphate (cGAMP) and DOX. The cationic liposomes with 8% DOTAP release cGAMP into the cytoplasm and increase the concentration of DOX in the tumor by 1.5 times compared with the free drug. Upon accumulation at the tumor site, the optimized liposomes induce immunogenic cell death (ICD) and stimulate the STING signaling, thereby improving the production of endogenous IFN‐I and promoting dendritic cell maturation to mobilize T cell immunity. The tumor growth inhibition rate is 86%, and the median survival time is 1.6‐fold prolonged. This study offers a strategy to enhance the DOX‐induced immune response by activating the STING pathway to supply IFN‐I.

Clinical applications of STING agonists in cancer immunotherapy: current progress and future prospects.

The STING (Stimulator of Interferon Genes) pathway is pivotal in activating innate immunity, making it a promising target for cancer immunotherapy. STING agonists have shown potential in enhancing immune responses, particularly in tumors resistant to traditional therapies. This scholarly review examines the diverse categories of STING agonists, encompassing CDN analogues, non-CDN chemotypes, CDN-infused exosomes, engineered bacterial vectors, and hybrid structures of small molecules-nucleic acids. We highlight their mechanisms, clinical trial progress, and therapeutic outcomes. While these agents offer significant promise, challenges such as toxicity, tumor heterogeneity, and delivery methods remain obstacles to their broader clinical use. Ongoing research and innovation are essential to overcoming these hurdles. STING agonists could play a transformative role in cancer treatment, particularly for patients with hard-to-treat malignancies, by harnessing the body's immune system to target and eliminate cancer cells.

Sulfate Radical Based In Situ Vaccine Boosts Systemic Antitumor Immunity via Concurrent Activation of Necroptosis and STING Pathway.

In situ vaccine (ISV) can provoke systemic anti-tumor immunity through the induction of immunogenic cell death (ICD). The development of ISV technology has been restricted by the limited and suboptimal ICD driven tumor antigen production which are currently relying on chemo-drugs, photo-/radio-sensitizers, oncolytic-virus and immunostimulatory agents. Herein, a sulfate radical (SO4 ·-) based ISV is reported that accomplishes superior tumor immunotherapy dispense from conventional approaches. The ISV denoted as P-Mn-LDH is constructed by intercalating peroxydisulfate (PDS, a precursor of SO4 ·-) into manganese layered double hydroxide nanoparticles (Mn-LDH). This design allows the stabilization of PDS under ambient condition, but triggers a Mn2+ mediated PDS decomposition in acidic tumor microenvironment (TME) to generate in situ SO4 ·-. Importantly, it is found that the SO4 ·- radicals not only effectively kill cancer cells, but also induce a necroptotic cell death pathway, leading to robust ICD signaling for eliciting adaptive immunity. Further, the P-Mn-LDH can activate the stimulator of interferon genes (STING) pathway to further boost anti-tumor immunity. Collectively, the P-Mn-LDH based ISV exhibited potent activity in inhibiting tumor growth and lung metastasis. When combined with immune checkpoint inhibitor, significant inhibition of distant tumors is achieved. This study underpins the promise of SO4 ·- based vaccine technology for cancer immunotherapy.

Assembly of 2′,3′-Cyclic guanosine Monophosphate-Adenosine monophosphate and their spontaneous intracellular disassembly for enhanced antitumor immunity via natural STING pathway activation

The stimulator of interferon genes (STING) pathway plays an important role in remodeling the immunosuppressive tumor microenvironment (TME). Cyclic dinucleotides (CDNs), the natural ligands of STING, activate innate immunity to enhance tumor immunogenicity. However, the anionic properties of CDNs result in poor membrane permeability, while their rapid metabolism by enzymes hinders the efficient targeting and activation of STING in vitro and in vivo. To improve the bioavailability and antitumor immunity of CDNs, we designed a hydrogen-bonding-based supramolecular approach for 2′,3′-cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP). Leveraging the synthetic molecules cytosine-uracil-hexane (CUH), we formulated supramolecular micelles of cGAMP via specific hydrogen bonds in aqueous solutions. Micelles comprising the CUH-cGAMP complex enhanced the biological efficacy of cGAMP by increasing its stability, thereby prolonging the activation of STING-mediated innate and adaptive immunity. We demonstrated that CUH-cGAMP stands as a promising candidate for immunotherapy, exhibiting significant inhibition of tumor growth in a CT26 syngeneic mouse model.

Interferon-induced factor 16 is essential in metastatic melanoma to maintain STING levels and the immune responses upon IFN-γ response pathway activation

BackgroundImmune checkpoint inhibitor (ICIs)-based therapies are the standard of care treatment for patients with metastatic melanoma (MM). The stimulator of interferon genes (STING) signaling pathway is critical in controlling immune...

The Role of STING-Mediated Activation of Dendritic Cells in Cancer Immunotherapy.

The signaling pathway that comprises cyclic guanosine monophosphate-adenosine monophosphate (cGAMP or GMP-AMP) synthase (cGAS) and Stimulator of Interferon Genes (STING) is emerging as a druggable target for immunotherapy, with tumor-resident dendritic cells (DC) playing a critical role in mediating its effects. The STING receptor is part of the DNA-sensing cellular machinery, that can trigger the secretion of pro-inflammatory mediators, priming effector T cells and initiating specific antitumor responses. Yet, recent studies have highlighted the dual role of STING activation in the context of cancer: STING can either promote antitumor responses or enhance tumor progression. This dichotomy often depends on the cell type in which cGAS-STING signaling is induced and the activation mode, namely acute versus chronic. Of note, STING activation at the DC level appears to be particularly important for tumor eradication. This review outlines the contribution of the different conventional and plasmacytoid DC subsets and describes the mechanisms underlying STING-mediated activation of DCs in cancer. We further highlight how the STING pathway plays an intricate role in modulating the function of DCs embedded in tumor tissue. Additionally, we discuss the strategies being employed to harness STING activation for cancer treatment, such as the development of synthetic agonists and nano-based delivery systems, spotlighting the current techniques used to prompt STING engagement specifically in DCs.

Cyclopeptide Inhibitors Target the N-Terminal Tail of STING and Alleviate Autoinflammation.

Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a crucial component of innate immunity that plays a vital role in protecting against pathogen infections and cellular stress. However, aberrant activation of cGAS-STING pathway is related to inflammatory and autoimmune diseases. Here, we developed cyclopeptide STING inhibitors by cyclizing the N-terminal tail (NTT) of STING. These cyclopeptides selectively inhibited the activation of STING pathway in human or murine cell lines. Mechanistically, the inhibitors directly bound to STING, and subsequently blocked the aggregation and activation of STING. In addition, the optimal inhibitor STi-2 significantly suppressed proinflammatory cytokine production and systemic inflammation in Trex1-/- mice. Overall, our work facilitates the development of specific inhibitors of STING as potential therapies for cGAS-STING associated autoinflammatory diseases.

STING Orchestrates EV-D68 Replication and Immunometabolism within Viral-Induced Replication Organelles.

Some respiratory viruses, such as Human Rhinovirus, SARS-CoV-2, and Enterovirus D-68 (EV-D68), share the feature of hijacking host lipids in order to generate specialised replication organelles (ROs) with unique lipid compositions to enable viral replication. We have recently uncovered a novel non-canonical function of the stimulator of interferon genes (STING) pathway, as a critical factor in the formation of ROs in response to HRV infection. The STING pathway is the main DNA virus sensing system of the innate immune system controlling the type I IFN machinery. Although it is well-characterised as part of the DNA sensor machinery, the STING function in RNA viral infections is largely unexplored. In the current study, we investigated whether other RO-forming RNA viruses, such as EV-D68 and SARS-CoV-2, can also utilise STING for their replication. Using genetic and pharmacological inhibition, we demonstrate that STING is hijacked by these viruses and is utilised as part of the viral replication machinery. STING also co-localises with glycolytic enzymes needed to fuel the energy for replication. The inhibition of STING leads to the modulation of glucose metabolism in EV-D68-infected cells, suggesting that it might also manipulate immunometabolism. Therefore, for RO-generating RNA viruses, STING seems to have non-canonical functions in membrane lipid re-modelling, and the formation of replication vesicles, as well as immunometabolism.

STING Agonist Delivered by Neutrophil Membrane-Coated Gold Nanoparticles Exerts Synergistic Tumor Inhibition with Radiotherapy.

Radiotherapy (RT) is one of the major treatments for cancers and a promising initiator of immune response. Gold nanoparticles are a promising radiosensitizer. In this study, we sought to optimize the drug delivery efficiency of gold nanoparticles and explore their function in delivering stimulator of interferon genes (STING) agonists with or without RT. Gold nanoparticles covalent to MSA-2 (MSA-Au) were mixed with cRGD-modified neutrophil membranes to obtain M-Au@RGD-NM. We explored the treatment efficiency of M-Au@RGD-NM combined with RT. Immune cell regulation and STING pathway activation were detected. We successfully prepared M-Au@RGD-NM with significant tumor suppression by induction of ROS and the resulting DNA damage. In vivo dynamic imaging showed that M-Au@RGD-NM was mainly targeted to radiated tumors. Tumor-bearing mice showed significant tumor inhibition following a combination therapy. M-Au@RGD-NM significantly activated the STING pathway and regulated the whole-body immune response. Locally radiated tumors showed dendritic cells mature, CD8+ T cells upregulation, and M1 polarization, with systematic immune response demonstrated by CD8+ T cell infiltration in abscopal tumors. In this study, we synthesized M-Au@RGD-NM loading MSA-2. Following characterization, we found that RT-based M-Au@RGD-NM treatment achieved good antitumor effects, tumor RT enhancement, and induction of an immune response via STING activation.

Hybrid nanoparticle-mediated simultaneous ROS scavenging and STING activation improve the antitumor immunity of in situ vaccines.

In situ vaccine (ISV) is a versatile and personalized local immunotherapeutic strategy. However, the compromised viability and function of dendritic cells (DCs) in a tumor microenvironment (TME) largely limit the therapeutic efficacy. We designed a hybrid nanoparticle-based ISV, which accomplished superior cancer immunotherapy via simultaneously scavenging reactive oxygen species (ROS) and activating the stimulator of interferon genes (STING) pathway in DCs. This ISV was constructed by encapsulating a chemodrug, SN38, into diselenide bond-bridged organosilica nanoparticles, followed by coating with a Mn2+-based metal phenolic network. We show that this ISV can activate the STING pathway through Mn2+ and SN38 comediated signaling and simultaneously scavenge preexisting H2O2 in the TME and Mn2+-catalyzed •OH by leveraging the antioxidant property of diselenide and polyphenol. This ISV effectively activated DCs and protected them from oxidative damage, leading to remarkable downstream T cell activation and systemic antitumor immunity. This work highlights a nanoparticle design that manipulates DCs in the TME for improving the ISV.