A Thermosensitive Bi‐Adjuvant Hydrogel Triggers Epitope Spreading to Promote the Anti‐Tumor Efficacy of Frameshift Neoantigens DOI Creative Commons

Yaohua Ke,

Kai Xin, Yaping Tao

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(14)

Published: Feb. 2, 2024

Abstract Tumor‐specific frameshift mutations encoding peptides (FSPs) are highly immunogenic neoantigens for personalized cancer immunotherapy, while their clinical efficacy is limited by immunosuppressive tumor microenvironment (TME) and self‐tolerance. Here, a thermosensitive hydrogel (FSP‐RZ‐BPH) delivering dual adjuvants R848 (TLR7/8 agonist) + Zn 2+ (cGAS‐STING designed to promote the of FSPs on murine forestomach (MFC). After peritumoral injection, FSP‐RZ‐BPH behaves as pH‐responsive sustained drug release at sites near effectively transform TME into an inflammatory type. orchestrates innate adaptive immunity activate dendritic cells in tumor‐draining lymph nodes increase number FSPs‐reactive effector memory T ( EM ) 2.9 folds. More importantly, these also exhibit responses nonvaccinated MFC. This epitope spreading effect contributes reduce self‐tolerance maintain long‐lasting anti‐tumor immunity. In MFC suppressive model, achieves 84.8% inhibition rate prolongs survival tumor‐bearing mice with 57.1% complete response rate. As preventive vaccine, can significantly delay growth. Overall, work identifies first time demonstrates bi‐adjuvant effective strategy boost bystander neoantigens.

Language: Английский

Targeting STING in dendritic cells alleviates psoriatic inflammation by suppressing IL-17A production DOI

Xiaoying Sun,

Liu Liu, Jiao Wang

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(7), P. 738 - 751

Published: May 28, 2024

Language: Английский

Citations

11
The cytosolic DNA‐sensing cGAS–STING pathway in neurodegenerative diseases DOI Creative Commons
Xiaofeng Guo, Lin Yang, Jiawei Wang

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(3)

Published: March 1, 2024

Abstract Background With the widespread prevalence of neurodegenerative diseases (NDs) and high rates mortality disability, it is imminent to find accurate targets for intervention. There growing evidence that neuroimmunity pivotal in pathology NDs interventions targeting hold great promise. Exogenous or dislocated nucleic acids activate cytosolic DNA sensor cyclic GMP‐AMP synthase (cGAS), activating stimulator interferon genes (STING). The activated STING triggers innate immune responses then cGAS‐STING signaling pathway links abnormal acid sensing response. Recently, numerous studies have shown neuroinflammation regulated by plays an essential role NDs. Aims In this review, we summarized mechanism focused on inhibitors cGAS‐STING. Conclusion important pathogenesis Inhibiting may provide new measures treatment

Language: Английский

Citations

9
TAX1BP1-dependent autophagic degradation of STING1 impairs anti-tumor immunity DOI
Ruoxi Zhang, Chunhua Yu,

Herbert J. Zeh

et al.

Autophagy, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

The activation of STING1 can lead to the production and secretion cytokines, initiating antitumor immunity. Here, we screened an ion channel ligand library identified tetrandrine, a bis-benzylisoquinoline alkaloid, as immunological adjuvant that enhances immunity by preventing autophagic degradation protein. This tetrandrine effect is independent its known function calcium or potassium blocker. Instead, inhibits lysosomal function, impairing cathepsin maturation, degradation. Proteomic analysis lysosomes TAX1BP1 novel receptor for proteolysis STING1. recognizes through physical interaction coiled-coil domain with cyclic dinucleotide binding Systematic mutation lysine (K) residues revealed K63-ubiquitination at K224 site ignites TAX1BP1-dependent Combined treatment agonists promotes converting "cold" pancreatic cancers into "hot" tumors. process associated enhanced cytokine release increased infiltration cytotoxic T-cells tumor microenvironment. mediated limited neutralizing antibodies type I interferon CD8+ T cells. Thus, these findings establish potential immunotherapeutic strategy against cancer

Language: Английский

Citations

1
Bioengineered Neutrophil Extinguisher Targets Cascade Immune Pathways of Macrophages for Alleviating Cytokine Storm in Pneumonia DOI
Anwei Zhou, Kerong Chen, Ya Gao

et al.

ACS Nano, Journal Year: 2023, Volume and Issue: 17(17), P. 16461 - 16477

Published: Aug. 19, 2023

Cytokine storm is a common complication of COVID-19 pneumonia and has been proven to contribute high mortality rates. However, current treatment approaches exhibit limited potential balance immune response overproduction inflammatory cytokines, leading poor therapeutic outcomes. Herein, smart bioengineered neutrophil, Extinguisher, composed live neutrophils encapsulating the liposome formulation NF-κB suppressor MLN4924 STING inhibitor H-151 (Lip@MH), developed for alleviating hyperinflammatory cytokine storm. Extinguisher inherits motility chemotaxis characteristics neutrophils, allowing specific delivery sustained release Lip@MH within inflamed tissues. Subsequently, effectively transports anti-inflammatory agents into macrophages synergistically inhibits pathways STING, decreased production cytokines. In vivo studies demonstrate that not only selectively accumulates at site caused by Pseudomonas aeruginosa-induced acute lung injury but factors through regulating NF-κB/STING signaling pathways, thereby calming Importantly, significantly improves benefits survival in mice with pneumonia. Therefore, represents an appropriate combination cell therapy immunoregulation intervention may bring insights

Language: Английский

Citations

22
cGAS-STING signaling pathway in intestinal homeostasis and diseases DOI Creative Commons
Yuchen Yang, Li Wang, Ivonne Peugnet-González

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 14, 2023

The intestinal mucosa is constantly exposed to commensal microbes, opportunistic pathogens, toxins, luminal components and other environmental stimuli. consists of multiple differentiated cellular extracellular that form a critical barrier, but also equipped for efficient absorption nutrients. Combination genetic susceptibility factors are known as involved in the pathogenesis diseases. innate immune system plays role recognition elimination potential threats by detecting pathogen-associated molecular patterns (PAMPs) damage-associated (DAMPs). This host defense facilitated pattern receptors (PRRs), which cyclic GMP-AMP synthase-stimulator interferon genes (cGAS-STING) pathway has gained attention due its sensing foreign double-stranded DNA (dsDNA) well dinucleotides (CDNs) produced bacteria. Upon binding with dsDNA, cGAS converts ATP GTP (cGAMP), binds STING activates TANK kinase 1 (TBK1) regulatory factor 3 (IRF3), inducing type I (IFN) nuclear kappa B (NF-κB)-mediated pro-inflammatory cytokines, have diverse effects on adaptive cells epithelial (IECs). However, opposite perspectives exist regarding cGAS-STING different Activation signaling associated worse clinical outcomes inflammation-associated diseases, while it protection against tumorigenesis certain infections. Therefore, understanding context-dependent mechanisms physiopathology crucial developing therapeutic strategies targeting pathway. review aims provide insight into recent findings protective detrimental roles

Language: Английский

Citations

17
cGLRs Join Their Cousins of Pattern Recognition Receptor Family to Regulate Immune Homeostasis DOI Open Access
Vijay Kumar, John H. Stewart

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1828 - 1828

Published: Feb. 2, 2024

Pattern recognition receptors (PRRs) recognize danger signals such as PAMPs/MAMPs and DAMPs to initiate a protective immune response. TLRs, NLRs, CLRs, RLRs are well-characterized PRRs of the host system. cGLRs have been recently identified PRRs. In humans, cGAS/STING signaling pathway is part cGLRs. cGAS recognizes cytosolic dsDNA PAMP or DAMP STING-dependent response comprising type 1 IFN release, NF-κB activation, autophagy, cellular senescence. The present article discusses emergence critical how they regulate responses. We examined role signaling, well-studied cGLR system, in activation following sections discuss dysregulation disease cross-talk with other maintains homeostasis. This understanding will lead design better vaccines immunotherapeutics for various diseases, including infections, autoimmunity, cancers.

Language: Английский

Citations

8
Induction of antiviral interferon-stimulated genes by neuronal STING promotes the resolution of pain in mice DOI Creative Commons

Manon Defaye,

Amyaouch Bradaia,

Nasser Abdullah

et al.

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(9)

Published: March 19, 2024

Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining resolution opioid analgesia, maladaptive processes occurring during can lead the transition pain. Here we found that activates cytosolic DNA-sensing protein stimulator of IFN genes (STING) dorsal root ganglion nociceptors. Neuronal activation STING promotes signaling through TANK-binding kinase 1 (TBK1) triggers an IFN-β response mediates resolution. Notably, mice expressing a nociceptor-specific gain-of-function mutation exhibited gene signature reduced nociceptor excitability inflammatory hyperalgesia KChIP1-Kv4.3 regulation. Our findings reveal role IFN-regulated KChIP1 downstream

Language: Английский

Citations

8
STING agonist-conjugated metal-organic framework induces artificial leukocytoid structures and immune hotspots for systemic antitumor responses DOI Creative Commons
Taokun Luo, Xiaomin Jiang, Yingjie Fan

et al.

National Science Review, Journal Year: 2024, Volume and Issue: 11(7)

Published: May 10, 2024

ABSTRACT Radiotherapy is widely used for cancer treatment, but its clinical utility limited by radioresistance and inability to target metastases. Nanoscale metal-organic frameworks (MOFs) have shown promise as high-Z nanoradiosensitizers enhance radiotherapy induce immunostimulatory regulation of the tumor microenvironment. We hypothesized that MOFs could deliver small-molecule therapeutics synergize with enhanced antitumor efficacy. Herein, we develop a robust nanoradiosensitizer, GA-MOF, conjugating STING agonist, 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (GA), on synergistic radiosensitization activation. GA-MOF demonstrated strong anticancer efficacy forming immune-cell-rich nodules (artificial leukocytoid structures) transforming them into hotspots radiotherapy. Further combination an immune checkpoint blockade suppressed distant tumors through systemic Our work not only demonstrates potent also provides detailed mechanisms regarding MOF distribution, regulatory pathways long-term effects.

Language: Английский

Citations

8
The interplay between autophagy and cGAS-STING signaling and its implications for cancer DOI Creative Commons
Maximilian Schmid, Patrick D. Fischer, Magdalena Engl

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: April 10, 2024

Autophagy is an intracellular process that targets various cargos for degradation, including members of the cGAS-STING signaling cascade. senses cytosolic double-stranded DNA and triggers innate immune response through type I interferons. Emerging evidence suggests autophagy plays a crucial role in regulating fine-tuning signaling. Reciprocally, pathway can actively induce canonical as well non-canonical forms autophagy, establishing regulatory network feedback mechanisms alter both autophagic pathway. The crosstalk between impacts wide variety cellular processes such protection against pathogenic infections neurodegenerative disease, autoinflammatory disease cancer. Here we provide comprehensive overview involved signaling, with specific focus on interactions two pathways their importance

Language: Английский

Citations

7
Deciphering microglial activation and neuronal apoptosis post‑traumatic brain injury: The role of TYROBP in inflammation regulation networks DOI Creative Commons
Xudong Zhou,

Huiping Song,

Jingjing He

et al.

Molecular Medicine Reports, Journal Year: 2024, Volume and Issue: 29(6)

Published: April 18, 2024

Traumatic Brain Injury (TBI) represents a significant public health challenge. Recovery from brain injury necessitates the collaborative efforts of various resident neural cells, predominantly microglia. The present study analyzed rat and mouse RNA expression micro‑arrays, high‑throughput sequencing single‑cell data sourced databases. To construct an inflammation regulation network around TYRO protein tyrosine kinase‑binding (TYROBP), to evaluate role TYROBP in cell death after TBI. These findings indicate that following TBI, neurons communicate with one another through CXC chemokine ligand (CXCL) CC (CCL) signaling pathways, employing paracrine mechanism activate activated microglia intensify pathological progression by releasing factors such as tumor necrosis factor α (TNF‑α), vascular endothelial growth transforming β via NF‑κB pathway. Cells co‑culture experiments demonstrated neurons, impaired mechanical injury, interact non‑contact mechanisms. Activated secrete cytokines, including TNF‑α, CXCL‑8 CCL2, which trigger inflammatory response facilitate neuronal apoptosis. gene knockout was reduce this interaction apoptosis rates.

Language: Английский

Citations

7