GPR162 activates STING dependent DNA damage pathway as a novel tumor suppressor and radiation sensitizer DOI Creative Commons
Yao Long,

Jiaxing Guo,

Jielin Chen

et al.

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

Published: Feb. 1, 2023

In the treatment of most malignancies, radiotherapy plays a significant role. However, resistance cancer cells to ionizing radiation (IR) is main reason for failure radiotherapy, which causes tumor recurrence and metastasis. this study, we confirmed that GPR162, an orphan receptor in G-protein-coupled family, acted as novel sensitizer by interacting with stimulator interferon genes (STING), targeted DNA damage responses, activated IRF3, accelerated activation type I system, promoted expression chemokines including CXCL10 CXCL4, inhibited occurrence development tumors. Interestingly, STING overexpression GPR162 was independent classical pathway cGAS. inhibitors could resist antitumor effect IR-induced mouse models. addition, solid tumors showed low GPR162. And higher indicated better prognosis patients lung adenocarcinoma, liver cancer, breast etc. summary, these results suggested may serve potential promoting radiotherapy-induced STING-IFN production increasing CXCL4 response, providing alternative strategy improving radiotherapy.

Language: Английский

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

214
The cGAS/STING Pathway: A Novel Target for Cancer Therapy DOI Creative Commons
Yu Gan, M Kellis, Shuangze Han

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 12

Published: Jan. 3, 2022

As a DNA receptor, cyclic GMP-AMP synthase (cGAS) plays crucial role in the immune system by recognizing abnormal cytoplasm and activating stimulator of interferon genes (STING) signaling pathway. This cascade reaction leads to an response produced type I other mediators. Recent advances research have enhanced our current understanding potential cGAS/STING pathway anticancer therapy; however, some cases, chronic STING activation may promote tumorigenesis. The present review article discusses biological mechanisms pathway, its dichotomous tumors, latest with respect agonists antagonists.

Language: Английский

Citations

117
Tumor-targeted delivery of a STING agonist improves cancer immunotherapy DOI Creative Commons

Youtong Wu,

Yan Fang, Wei Qi

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(49)

Published: Nov. 28, 2022

The cGAS-STING pathway is essential for immune defense against microbial pathogens and malignant cells; as such, STING an attractive target cancer immunotherapy. However, systemic administration of agonists poses safety issues while intratumoral injection limited by tumor accessibility. Here, we generated antibody-drug conjugates (ADCs) conjugating a agonist through cleavable linker to antibodies targeting cells. Systemic these ADCs was well tolerated exhibited potent antitumor efficacy in syngeneic mouse models. ADC further synergized with anti-PD-L1 antibody achieve superior efficacy. promoted multiple aspects innate adaptive responses, including activation dendritic cells, T natural killer cells promotion M2 M1 polarization tumor-associated macrophages. These results provided the proof concept clinical development ADCs.

Language: Английский

Citations

114
Maintaining manganese in tumor to activate cGAS-STING pathway evokes a robust abscopal anti-tumor effect DOI
Chao Wang, Zhaoyi Sun,

Chenxuan Zhao

et al.

Journal of Controlled Release, Journal Year: 2021, Volume and Issue: 331, P. 480 - 490

Published: Feb. 5, 2021

Language: Английский

Citations

106
Biochemistry, Cell Biology, and Pathophysiology of the Innate Immune cGAS–cGAMP–STING Pathway DOI Open Access
Christopher Ritchie,

Jacqueline A. Carozza,

Lingyin Li

et al.

Annual Review of Biochemistry, Journal Year: 2022, Volume and Issue: 91(1), P. 599 - 628

Published: March 15, 2022

In the decade since discovery of innate immune cyclic GMP-AMP synthase (cGAS)-2'3'-cyclic (cGAMP)-stimulator interferon genes (STING) pathway, its proper activation and dysregulation have been rapidly implicated in many aspects human disease. Understanding biochemical, cellular, regulatory mechanisms this pathway is critical to developing therapeutic strategies that either harness it boost defense or inhibit prevent unwanted inflammation. review, we first discuss how second messenger cGAMP synthesized by cGAS response double-stranded DNA cGAMP's subsequent cell-type-dependent STING signaling cascades with differential physiological consequences. We then review as an immunotransmitter mediates tightly controlled cell-cell communication being exported from producing cells imported into responding via cell-type-specific transporters. Finally, which thecGAS-cGAMP-STING responds different sources mislocalized pathogen defense, cancer, autoimmune diseases.

Language: Английский

Citations

83
Ultrasound-responsive low-dose doxorubicin liposomes trigger mitochondrial DNA release and activate cGAS-STING-mediated antitumour immunity DOI Creative Commons
Chaoyu Wang, Ruoshi Zhang, Jia He

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 30, 2023

Abstract DNA derived from chemotherapeutics-killed tumor cells is one of the most important damage-associated molecular patterns that can activate cGAS-STING (cyclic GMP-AMP synthase—stimulator interferon genes) pathway in antigen-presenting (APCs) and promote antitumor immunity. However, conventional chemotherapy displays limited cell killing ineffective transfer stable to APCs. Here we show liposomes loaded with an optimized ratio indocyanine green doxorubicin, denoted as LID, efficiently generate reactive oxygen species upon exposure ultrasound. LID plus ultrasound enhance nuclear delivery induce mitochondrial oxidation, oxidized APCs for effective activation signaling. Depleting or knocking out STING compromises Furthermore, systemic injection over lead targeted cytotoxicity activation, eliciting potent T immunity, which combination immune checkpoint blockade leads regression bilateral MC38, CT26, orthotopic 4T1 tumors female mice. Our study sheds light on importance STING-mediated immunity may inspire development more strategies cancer immunotherapy.

Language: Английский

Citations

78
DNA in extracellular vesicles: from evolution to its current application in health and disease DOI Creative Commons
Jamal Ghanam, Venkatesh Kumar Chetty, Lennart Barthel

et al.

Cell & Bioscience, Journal Year: 2022, Volume and Issue: 12(1)

Published: March 28, 2022

Extracellular vesicle (EV) secretion is a highly conserved evolutionary trait in all organisms the three domains of life. The packaging and release EVs appears to be bulk-flow process which takes place mainly under extreme conditions. participate horizontal gene transfer, supports survival prokaryotic eukaryotic microbes. In higher eukaryotes, almost cells secrete heterogeneous population loaded with various biomolecules. EV typically cancer microenvironments, promoting tumor progression metastasis. are now recognized as additional mediators autocrine paracrine communication health disease. this context, proteins RNAs have been studied most, but extracellular DNA (EV-DNA) has started gain importance last few years. review, we summarize new findings related loading mechanism(s), localization, post-shedding function EV-DNA. We also discuss feasibility using EV-DNA biomarker when performing liquid biopsy, at same time emphasizing lack data from clinical trials regard. Finally, outline potential uptake its interaction host genome promising tool for understanding mechanisms evolution.

Language: Английский

Citations

75
TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models DOI Creative Commons
Jun-Yan Li, Yin Zhao, Sha Gong

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 16, 2023

Abstract Although radiotherapy can promote antitumour immunity, the mechanisms underlying this phenomenon remain unclear. Here, we demonstrate that expression of E3 ubiquitin ligase, tumour cell-intrinsic tripartite motif-containing 21 (TRIM21) in tumours, is inversely associated with response to radiation and CD8 + T cell-mediated immunity nasopharyngeal carcinoma (NPC). Knockout TRIM21 modulates cGAS/STING cytosolic DNA sensing pathway, potentiates antigen-presenting capacity NPC cells, activates cytotoxic radiation. Mechanistically, promotes degradation mitochondrial voltage-dependent anion-selective channel protein 2 (VDAC2) via K48-linked ubiquitination, which inhibits pore formation by VDAC2 oligomers for (mtDNA) release, thereby inhibiting type-I interferon responses following exposure. In patients NPC, high was poor prognosis early relapse after radiotherapy. Our findings reveal a critical role radiation-induced providing potential targets improving efficacy NPC.

Language: Английский

Citations

65
4-octyl itaconate as a metabolite derivative inhibits inflammation via alkylation of STING DOI Creative Commons
Weizhen Li, Yangguang Li, Jiaqi Kang

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112145 - 112145

Published: Feb. 28, 2023

The Krebs cycle-derived metabolite itaconate, whose production is catalyzed by immune response gene 1 (IRG1), has potential to link immunity and metabolism in activated macrophages through alkylation or competitive inhibition of target proteins. In support this, our previous study demonstrated that the stimulator interferon genes (STING) signaling platform functions as a hub macrophage profound impact on prognosis sepsis. Interestingly, we find an endogenous immunomodulator, can significantly inhibit activation STING signaling. Moreover, 4-octyl itaconate (4-OI), which permeable derivative, alkylate cysteine sites 65, 71, 88, 147 STING, thereby inhibiting its phosphorylation. Furthermore, 4-OI inflammatory factors sepsis models. Our results broaden knowledge role IRG1-itaconate axis immunomodulation highlight derivatives therapeutic agents

Language: Английский

Citations

60
Macrophage STING signaling promotes NK cell to suppress colorectal cancer liver metastasis via 4-1BBL/4-1BB co-stimulation DOI Creative Commons
Yu Sun,

Haoran Hu,

Zheng Liu

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(3), P. e006481 - e006481

Published: March 1, 2023

Background and aims Macrophage innate immune response plays an important role in tumorigenesis. However, the mechanism of macrophage STING signaling modulating tumor microenvironment to suppress growth at secondary sites remains largely unclear. Methods expression was assessed liver samples from patients with colorectal cancer (CRC) metastasis. Global or myeloid stimulator interferon gene (STING)-deficient mice, NOD-like receptor protein 3 (NLRP3)-deficient wild-type (WT) mice were subjected a mouse model CRC metastasis by intrasplenic injection murine colon carcinoma cells (MC38). Liver non-parenchymal including macrophages natural killer (NK) isolated for flow cytometry analysis. Bone marrow-derived pretreated MC38 co-cultured splenic NK vitro studies. Results Significant activation detected adjacent tissues intrahepatic macrophages. STING-deficient had exacerbated shorten survival, decreased infiltration impaired antitumor function cells. Depletion WT animals increased their metastatic burden, while no significant effects observed mice. contributed secretion interleukin (IL)-18 IL-1β macrophages, which optimized activity promoting 4-1BBL 4-1BB cells, respectively. Moreover, treatment activated NLRP3 signaling, inhibited depletion. Myeloid deficiency burden suppressed its agonist effectively SITNG-deficient Conclusions We demonstrated that promoted NLRP3-mediated IL-18 production optimize via co-stimulation 4-1BBL/4-1BB.

Language: Английский

Citations

56