Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(6), P. 5977 - 6039

Published: Feb. 2, 2022

The stimulator of interferon genes (STING) cellular signaling pathway is a promising target for cancer immunotherapy. Activation the intracellular STING protein triggers production multifaceted array immunostimulatory molecules, which, in proper context, can drive dendritic cell maturation, antitumor macrophage polarization, T priming and activation, natural killer vascular reprogramming, and/or death, resulting immune-mediated tumor elimination generation immune memory. Accordingly, there significant amount ongoing preclinical clinical research toward further understanding role surveillance as well development modulators strategy to stimulate immunity. Yet, efficacy agonists limited by many drug delivery pharmacological challenges. Depending on class agonist desired administration route, these may include poor stability, immunocellular toxicity, immune-related adverse events, or lymph node targeting retention, low uptake delivery, complex dependence magnitude kinetics signaling. This review provides concise summary pathway, highlighting recent biological developments, immunological consequences, implications delivery. also offers critical analysis an expanding arsenal chemical strategies that are being employed enhance efficacy, safety, utility lastly draws attention several opportunities therapeutic advancements.

Language: Английский

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Engineering Radiosensitizer‐Based Metal‐Phenolic Networks Potentiate STING Pathway Activation for Advanced Radiotherapy

Advanced Materials, Journal Year: 2021, Volume and Issue: 34(10)

Published: Dec. 29, 2021

Radiotherapy, a mainstay of first-line cancer treatment, suffers from its high-dose radiation-induced systemic toxicity and radioresistance caused by the immunosuppressive tumor microenvironment. The synergy between radiosensitization immunomodulation may overcome these obstacles for advanced radiotherapy. Here, authors propose cooperated with stimulator interferon genes (STING) pathway activation strategy fabricating novel lanthanide-doped radiosensitizer-based metal-phenolic network, NaGdF4 :Nd@NaLuF4 @PEG-polyphenol/Mn (DSPM). amphiphilic PEG-polyphenol successfully coordinates (radiosensitizer) Mn2+ via robust coordination. After cell internalization, pH-responsive disassembly DSPM triggers release their payloads, wherein radiosensitizer sensitizes cells to X-ray promote STING activation. This remarkably benefits dendritic maturation, anticancer therapeutics in primary tumors, accompanied immune therapeutic performance against metastatic tumors. Therefore, powerful mediated immunostimulation is highlighted here optimize

Language: Английский

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Manganese‐Based Tumor Immunotherapy

Advanced Materials, Journal Year: 2022, Volume and Issue: 35(19)

Published: Sept. 19, 2022

Abstract As an essential micronutrient, manganese (Mn) participates in various physiological processes and plays important roles host immune system, hematopoiesis, endocrine function, oxidative stress regulation. Mn‐based nanoparticles are considered to be biocompatible show versatile applications nanomedicine, particular utilized tumor immunotherapy the following ways: 1) acting as a nanocarrier deliver immunotherapeutic agents for immunotherapy; 2) serving adjuvant regulate microenvironment enhance 3) activating host's system through cGAS‐STING pathway trigger 4) real‐time monitoring effect by magnetic resonance imaging (MRI) since Mn 2+ ions ideal MRI contrast agent which can significantly T 1 ‐weighted signal after binding proteins. This comprehensive review focuses on most recent progress of nanoplatforms immunotherapy. The characteristics first discussed guide design multifunctional nanoplatforms. Then biomedical nanoplatforms, including alone, immunotherapy‐involved multimodal synergistic therapy, imaging‐guided detail. Finally, challenges future developments highlighted.

Language: Английский

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A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Sept. 28, 2022

Abstract cGAS-STING pathway is a key DNA-sensing machinery and emerges as promising target to overcome the immunoresistance of solid tumors. Here we describe bovine serum albumin (BSA)/ferritin-based nanoagonist incorporating manganese (II) ions β-lapachone, which cooperatively activates signaling in dendritic cells (DCs) elicit robust adaptive antitumor immunity. Mn 2+ -anchored mannose-modified BSAs β-lapachone-loaded ferritins are crosslinked afford bioresponsive protein nanoassemblies, dissociate into monodispersive units acidic perivascular tumor microenvironment (TME), thus enabling enhanced penetration spatiotemporally controlled β-lapachone delivery DCs cells, respectively. causes immunogenic cell apoptosis releases abundant dsDNA TME, while enhances sensitivity cGAS augments STING trigger downstream immunostimulatory signals. The tumor-specific T cell-mediated immune response against poorly tumors vivo, offering approach for immunotherapy clinics.

Language: Английский

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Manganese-phenolic nanoadjuvant combines sonodynamic therapy with cGAS-STING activation for enhanced cancer immunotherapy

Nano Today, Journal Year: 2022, Volume and Issue: 43, P. 101405 - 101405

Published: Jan. 25, 2022

Language: Английский

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Delivery of STING agonists for adjuvanting subunit vaccines

Advanced Drug Delivery Reviews, Journal Year: 2021, Volume and Issue: 179, P. 114020 - 114020

Published: Oct. 29, 2021

Adjuvant is an essential component in subunit vaccines. Many agonists of pathogen recognition receptors have been developed as potent adjuvants to optimize the immunogenicity and efficacy Recently discovered cyclic GMP-AMP synthase-stimulator interferon genes (cGAS-STING) pathway has attracted much attention it a key mediator for modulating immune responses. Vaccines adjuvanted with STING are found mediate robust defense against infections cancer. In this review, we first discuss mechanisms context vaccination. Next, present recent progress novel agonist discovery delivery strategies. We next highlight work optimizing while minimizing toxicity agonist-assisted vaccines protection infectious diseases or treatment Finally, share our perspectives current issues future directions further developing adjuvanting

Language: Английский

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Biomineralized MnO₂ Nanoplatforms Mediated Delivery of Immune Checkpoint Inhibitors with STING Pathway Activation to Potentiate Cancer Radio-Immunotherapy

ACS Nano, Journal Year: 2023, Volume and Issue: 17(5), P. 4495 - 4506

Published: Feb. 27, 2023

Radiotherapy (RT), as one of the main methods in clinical treatment various malignant tumors, would induce systemic immunotherapeutic effects by triggering immunogenic cell death (ICD) cancer cells. However, antitumor immune responses produced RT-induced ICD alone usually are not robust enough to eliminate distant tumors and thus ineffective against metastases. Herein, a biomimetic mineralization method for facile synthesis MnO2 nanoparticles with high anti-programmed ligand 1 (αPDL1) encapsulation efficiency (αPDL1@MnO2) is proposed reinforce responses. This therapeutic nanoplatforms-mediated RT can significantly improve killing tumor cells effectively evoke overcoming hypoxia-induced radio-resistance reprogramming immunosuppressive microenvironment (TME). Furthermore, released Mn2+ ions from αPDL1@MnO2 under acidic pH activate cyclic GMP-AMP synthase (cGAS)-stimulator interferon genes (STING) pathway facilitate dendritic (DCs) maturation. Meanwhile, αPDL1 further promote intratumoral infiltration cytotoxic T lymphocytes (CTLs) trigger responses, resulting strong abscopal effect inhibit Overall, biomineralized MnO2-based nanoplatforms offer simple strategy TME modulation activation, which promising enhanced immunotherapy.

Language: Английский

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Intracellular Self‐Assembly Driven Nucleus‐Targeted Photo‐Immune Stimulator with Chromatin Decompaction Function for Robust Innate and Adaptive Antitumor Immunity

Advanced Functional Materials, Journal Year: 2022, Volume and Issue: 32(17)

Published: March 4, 2022

Abstract Efficient nuclear DNA damage and release is highly recommended to improve the photodynamic immunotherapy by eliciting innate immune response yet remains challenging. Herein, an intracellular self‐assembly driven nucleus‐targeted photo‐immune stimulator (PIS) with chromatin decompaction function reported for adaptive antitumor immunity co‐activation. The PIS consists of vorinostat (SAHA)‐loaded manganese‐porphyrin metal‐organic framework (Mn (III)‐TCPP MOF) further modification AS1411 aptamer. can be efficiently internalized tumor cells disassembled under overexpressed glutathione (GSH). Notably, released able self‐assembled photosensitizer TCPP in situ within cells, driving delivery TCPP; meanwhile, loaded SAHA induce decompaction, cooperatively promoting TCPP‐mediated cytosolic laser irradiation. In addition, manganese ions 2+ ) enhance DNA/cyclic GMP‐AMP synthase (cGAS)‐stimulator interferon gene (STING) pathway mediated immunity, which synergizes PDT‐induced immunogenic cell death achieve co‐activation immunity. Compared traditional PDT, PDT system show significantly enhanced efficacy inhibiting primary growth distant metastasis several xenograft models, mechanistically maturation dendritic infiltration natural killer cell, cytotoxic T lymphocytes.

Language: Английский

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Radiation-induced tumor immune microenvironments and potential targets for combination therapy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 19, 2023

As one of the four major means cancer treatment including surgery, radiotherapy (RT), chemotherapy, immunotherapy, RT can be applied to various cancers as both a radical and an adjuvant before or after surgery. Although is important modality for treatment, consequential changes caused by in tumor microenvironment (TME) have not yet been fully elucidated. RT-induced damage cells leads different outcomes, such survival, senescence, death. During RT, alterations signaling pathways result local immune microenvironment. However, some are immunosuppressive transform into phenotypes under specific conditions, leading development radioresistance. Patients who radioresistant respond poorly may experience progression. Given that emergence radioresistance inevitable, new radiosensitization treatments urgently needed. In this review, we discuss irradiated TME regimens describe existing potential molecules could targeted improve therapeutic effects RT. Overall, review highlights possibilities synergistic therapy building on research.

Language: Английский

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Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

动物学研究, Journal Year: 2023, Volume and Issue: 44(1), P. 183 - 218

Published: Jan. 1, 2023

The innate immune system protects the host from external pathogens and internal damage in various ways. cGAS-STING signaling pathway, comprised of cyclic GMP-AMP synthase (cGAS), stimulator interferon genes (STING), downstream adaptors, plays an essential role protective defense against microbial DNA damaged-associated is responsible for immune-related diseases. After binding with DNA, cytosolic cGAS undergoes conformational change DNA-linked liquid-liquid phase separation to produce 2'3'-cGAMP activation endoplasmic reticulum (ER)-localized STING. However, further studies revealed that predominantly expressed nucleus strictly tethered chromatin prevent nuclear functions differently cytosolic-localized cGAS. Detailed delineation this including its structure, signaling, regulatory mechanisms, great significance fully understand diversity will be benefit treatment inflammatory diseases cancer. Here, we review recent progress on above-mentioned perspectives pathway discuss new avenues study.

Language: Английский

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