TET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer DOI Creative Commons
Hongwei Lv,

Qianni Zong,

Cian Chen

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 4, 2024

Abstract Induction of tumor vascular normalization is a crucial measure to enhance immunotherapy efficacy. cGAS-STING pathway vital for anti-tumor immunity, but its role in vasculature unclear. Herein, using preclinical liver cancer models Cgas / Sting -deficient male mice, we report that the interdependence between cGAS and host STING mediates immune response. Mechanistically, TET2 mediated IL-2/STAT5A signaling epigenetically upregulates expression produces cGAMP. Subsequently, cGAMP transported via LRRC8C channels activate endothelial cells, enhancing recruitment transendothelial migration lymphocytes. In vivo studies mice also reveal administration vitamin C, promising anti-cancer agent, stimulates activity, induces enhances efficacy anti-PD-L1 therapy alone or combination with IL-2. Our findings elucidate crosstalk cells microenvironment, providing strategies combinational cancer.

Language: Английский

The cGAS–STING pathway as a therapeutic target in inflammatory diseases DOI Open Access
Alexiane Decout, Jason D. Katz,

Shankar Venkatraman

et al.

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 21(9), P. 548 - 569

Published: April 8, 2021

Language: Английский

Citations

1369
Structures and Mechanisms in the cGAS-STING Innate Immunity Pathway DOI Creative Commons
Xuewu Zhang, Xiao‐chen Bai, Zhijian J. Chen

et al.

Immunity, Journal Year: 2020, Volume and Issue: 53(1), P. 43 - 53

Published: July 1, 2020

Language: Английский

Citations

511
Roles of natural killer cells in immunity to cancer, and applications to immunotherapy DOI
Natalie K. Wolf, Djem Kissiov, David H. Raulet

et al.

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 23(2), P. 90 - 105

Published: May 30, 2022

Language: Английский

Citations

301
The cGAS–STING pathway and cancer DOI

Natasha Samson,

Andrea Ablasser

Nature Cancer, Journal Year: 2022, Volume and Issue: 3(12), P. 1452 - 1463

Published: Dec. 12, 2022

Language: Английский

Citations

297
Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy DOI
Kyle M. Garland, Taylor L. Sheehy, John T. Wilson

et al.

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

Citations

211
The STING1 network regulates autophagy and cell death DOI Creative Commons
Ruoxi Zhang, Rui Kang, Daolin Tang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: June 2, 2021

Cell death and immune response are at the core of life. In past decades, endoplasmic reticulum (ER) protein STING1 (also known as STING or TMEM173) was found to play a fundamental role in production type I interferons (IFNs) pro-inflammatory cytokines DNA derived from invading microbial pathogens damaged hosts by activating multiple transcription factors. addition this well-known function infection, inflammation, immunity, emerging evidence suggests that STING1-dependent signaling network is implicated health disease regulating autophagic degradation various cell modalities (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, mitotic death, immunogenic [ICD]). Here, we outline latest advances our understanding mechanisms pathways autophagy which may shed light on new targets for therapeutic interventions.

Language: Английский

Citations

171
Role of the cGAS–STING pathway in systemic and organ-specific diseases DOI Open Access
Sladjana Skopelja‐Gardner, Jie An, Keith B. Elkon

et al.

Nature Reviews Nephrology, Journal Year: 2022, Volume and Issue: 18(9), P. 558 - 572

Published: June 22, 2022

Language: Английский

Citations

170
The interactions between cGAS-STING pathway and pathogens DOI Creative Commons

Zhangliang Cheng,

Tong Dai, Xuelin He

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: June 10, 2020

Abstract Cytosolic DNA is an indicator of pathogen invasion or damage. The cytosolic sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) detects and then mediates downstream immune responses through the molecule stimulator interferon genes (STING, also known as MITA, MPYS, ERIS TMEM173). Recent studies focusing on roles cGAS-STING pathway in evolutionary distant species have partly sketched how mammalian pathways are shaped revealed its evolutionarily conserved mechanism combating pathogens. Both this pathogens developed sophisticated strategies to counteract each other for their survival. Here, we summarise current knowledge interactions between from both mechanistic perspectives. Deeper insight into these might enable us clarify pathogenesis certain infectious diseases better harness antimicrobial methods.

Language: Английский

Citations

161
Cytosolic DNA sensing by cGAS: regulation, function, and human diseases DOI Creative Commons
Le Yu, Pengda Liu

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: April 30, 2021

Abstract Sensing invasive cytosolic DNA is an integral component of innate immunity. cGAS was identified in 2013 as the major sensor that binds dsDNA to catalyze synthesis a special asymmetric cyclic-dinucleotide, 2′3′-cGAMP, secondary messenger bind and activate STING for subsequent production type I interferons other immune-modulatory genes. Hyperactivation signaling contributes autoimmune diseases but serves adjuvant anticancer immune therapy. On hand, inactivation causes deficiency sense clear viral bacterial infection creates tumor-prone microenvironment facilitate tumor evasion surveillance. Thus, activation tightly controlled. In this review, we summarize up-to-date multilayers regulatory mechanisms governing activation, including pre- post-translational regulations, cGAS-binding proteins, additional regulators such ions small molecules. We will also reveal pathophysiological function its product cGAMP human diseases. hope provide review recent research advances biology cGAS-targeted therapies

Language: Английский

Citations

152
Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway DOI Creative Commons
Jeonghan Kim, Ho‐Shik Kim, Jay H. Chung

et al.

Experimental & Molecular Medicine, Journal Year: 2023, Volume and Issue: 55(3), P. 510 - 519

Published: March 24, 2023

In addition to constituting the genetic material of an organism, DNA is a tracer for recognition foreign pathogens and trigger innate immune system. cGAS functions as sensor double-stranded fragments initiates response via adaptor protein STING. The cGAS-STING pathway not only defends cells against various DNA-containing but also modulates many pathological processes caused by ectopic localization self-DNA, such cytosolic mitochondrial (mtDNA) extranuclear chromatin. addition, macrophages can cause inflammation forming class complexes called inflammasomes, activation NLRP3 inflammasome requires release oxidized mtDNA. immunity related mtDNA mediated macropores that are formed on outer membrane mitochondria VDAC oligomerization. These specifically in stress tissue damage, inhibition oligomerization mitigates this inflammatory response. rapidly expanding area research mechanisms which released triggers has revealed new treatment strategies also, surprisingly, neurodegenerative diseases amyotrophic lateral sclerosis.

Language: Английский

Citations

150