At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment DOI Creative Commons
Tatyana V. Korneenko, Nikolay B. Pestov, Ivan Nevzorov

и другие.

Pharmaceuticals, Год журнала: 2023, Номер 16(12), С. 1675 - 1675

Опубликована: Дек. 1, 2023

The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic systems that is activated in response to viral invasion and/or damage integrity nuclear envelope. key outcome this production interferon, which subsequently stimulates transcription hundreds genes. In oncology, situation complex because may serve either anti- or pro-oncogenic roles, depending on context. prevailing understanding when immune by sensing DNA, such as DNA released from ruptured micronuclei, it results attracts cytotoxic cells destroy tumors. However, tumor have adjusted significant chromosomal instability, particularly relapsed, treatment-resistant cancers, often supports cancer progression, fostering epithelial-to-mesenchymal transition (EMT). Here, we review intricate terms its association with giving special attention pancreatic ductal adenocarcinoma and gliomas. As development new cGAS-STING-modulating small molecules immunotherapies oncolytic viruses involves serious challenges, highlight several recent fundamental discoveries, proton-channeling function STING. These discoveries guiding lights for potential pharmacological advancements.

Язык: Английский

cGAS–STING, an important signaling pathway in diseases and their therapy DOI Creative Commons
Qijie Li,

Ping Wu,

Qiujing Du

и другие.

MedComm, Год журнала: 2024, Номер 5(4)

Опубликована: Март 23, 2024

Abstract Since cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway was discovered in 2013, great progress has been made to elucidate the origin, function, and regulating mechanism cGAS–STING past decade. Meanwhile, triggering transduction mechanisms have continuously illuminated. plays a key role human diseases, particularly DNA‐triggered inflammatory making it potentially effective therapeutic target for inflammation‐related diseases. Here, we aim summarize ancient origin defense mechanism, as well triggers, transduction, cGAS–STING. We will also focus on important roles signal under pathological conditions, such infections, cancers, autoimmune neurological visceral inflammations, review drug development targeting pathway. The main directions potential obstacles research diseases cancers be discussed. These advancements expand our understanding cGAS–STING, provide theoretical basis further exploration open up new strategies promising intervention multiple

Язык: Английский

Процитировано

23
IUPHAR ECR review: The cGAS-STING pathway: Novel functions beyond innate immune and emerging therapeutic opportunities DOI Creative Commons

He Xu,

Abdalla M. Wedn, Jian Wang

и другие.

Pharmacological Research, Год журнала: 2024, Номер 201, С. 107063 - 107063

Опубликована: Янв. 11, 2024

Stimulator of interferon genes (STING) is a crucial innate immune sensor responsible for distinguishing pathogens and cytosolic DNA, mediating signaling pathways to defend the host. Recent studies have revealed additional regulatory functions STING beyond its immune-related activities, including regulation cellular metabolism, DNA repair, senescence, autophagy various cell deaths. These findings highlight broader implications in physiology role immunity. Currently, approximately 10 agonists entered clinical stage. Unlike inhibitors, which maximum inhibition limit, potential infinite amplification. complex process that requires precise ensure balanced responses prevent detrimental autoinflammation. research on structural mechanism autoinhibition negative by adaptor protein 1 (AP-1) provides valuable insights into different effects under physiological pathological conditions, offering new perspective developing drugs. Herein, we present comprehensive overview molecular mechanisms regulation, along with updated details mechanisms. We discuss these regulations diseases, emphasizing importance feasibility targeting immunity-dependent or immunity-independent STING. Moreover, current trend drug development key points research, basic translational related

Язык: Английский

Процитировано

14
STING agonist inflames the cervical cancer immune microenvironment and overcomes anti-PD-1 therapy resistance DOI Creative Commons
Tianye Li, Weijiang Zhang,

Mengke Niu

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Март 14, 2024

Background Cervical cancer poses a significant global threat to women’s health. However, current therapeutic interventions, such as radiotherapy, chemotherapy, surgical resection, and immune checkpoint inhibitors, face limitations in the advanced stages of disease. Given immunosuppressive microenvironment cervical cancer, it is imperative explore novel perspectives. In this regard, STING agonists have emerged promising candidates. Methods The expression profiles clinicopathological data were obtained from Cancer Genome Atlas (TCGA) Gene Expression Omnibus (GEO) datasets. Prognostic analysis downstream genes (CCL5, CXCL9, CXCL10) infiltration conducted using Kaplan-Meier Plotter, ESTIMATE, deconvo_CIBERSOR . Single-cell RNA-seq (scRNA-seq) was evaluate potential MSA-2 treatment employing SingleR, chi-squared test, Set Enrichment Analysis (GSEA). Cellular interaction utilized CellChat package assess potentiation cellular following administration. Murine tumor models involving U14 TC-1, conducted, IF tissue subsequently status after treatment. Results Prognosis correlated with elevated genes, indicating prolonged survival reduced recurrence. These positively infiltration, influencing stromal scores, estimate scores. Specific cell populations, including CD8 + T cells, M1-type macrophages, NK follicular helper associated genes. scRNA-seq classic immune-excluded model revealed that exerts priming activating functions on vital components within TME, intensifies their intercellular communications. vivo assay ultimately demonstrated MSA-2, either standalone or combination anti-PD-1, effectively suppressed growth subcutaneous tumors. Moreover, strategy significantly augmented efficacy compared anti-PD-1 monotherapy by eliciting robust antitumor response. Conclusion This study highlights pivotal role pathway reshaping cancer. Combining inhibitors presents transformative approach, holding promise for improved prognosis. Further investigations are warranted broader landscape long-term effects

Язык: Английский

Процитировано

8
STING in Cancer Immunoediting: Modeling Tumor-Immune Dynamics Throughout Cancer Development DOI Creative Commons
Xiao Zhang, Yan Chen,

Xi Liu

и другие.

Cancer Letters, Год журнала: 2025, Номер 612, С. 217410 - 217410

Опубликована: Янв. 16, 2025

Язык: Английский

Процитировано

1
Enhancing immunotherapy outcomes by targeted remodeling of the tumor microenvironment via combined cGAS-STING pathway strategies DOI Creative Commons
Mingqing Huang,

Zhuocen Cha,

Rui Liu

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Май 16, 2024

Immune checkpoint inhibitors (ICIs) represent a groundbreaking advance in the treatment of malignancies such as melanoma and non-small cell lung cancer, showcasing substantial therapeutic benefits. Nonetheless, efficacy ICIs is limited to small subset patients, primarily benefiting those with “hot” tumors characterized by significant immune infiltration. The challenge converting “cold” tumors, which exhibit minimal activity, into enhance their responsiveness critical complex area current research. Central this endeavor activation cGAS-STING pathway, pivotal nexus between innate adaptive immunity. This pathway’s promotes production type I interferon (IFN) recruitment CD8 + T cells, thereby transforming tumor microenvironment (TME) from “hot”. review comprehensively explores role reconditioning TME, detailing underlying mechanisms immunity highlighting contributions various cells Furthermore, we delve latest clinical research on STING agonists potential combination therapies, targeting pathway. discussion concludes an examination challenges facing advancement promising trials pressing issues within signaling pathway

Язык: Английский

Процитировано

8
Nanocarrier-mediated modulation of cGAS-STING signaling pathway to disrupt tumor microenvironment DOI
Sai Kiran S. S. Pindiprolu,

Madhu Tanya Singh,

Magham Sai Varshini

и другие.

Naunyn-Schmiedeberg s Archives of Pharmacology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 5, 2025

Язык: Английский

Процитировано

0
CDK4/6 Alters TBK1 Phosphorylation to Inhibit the STING Signaling Pathway in Prostate Cancer DOI
Wei Li, Feng Guo,

Ruijiang Zeng

и другие.

Cancer Research, Год журнала: 2024, Номер 84(16), С. 2588 - 2606

Опубликована: Июнь 11, 2024

The efficacy of immunotherapy in patients with prostate cancer is limited due to the "cold" tumor microenvironment and paucity neoantigens. STING-TBK1-IRF3 signaling axis involved innate immunity has been increasingly recognized as a candidate target for immunotherapy. Here, we found that treatment CDK4/6 inhibitors stimulates STING pathway enhances antitumor effect agonists cancer. Mechanistically, phosphorylated TBK1 at S527 inactivate independent RB1 cells. CDK4/6-mediated phosphorylation S249/T252 also induced interaction diminish S172, which suppressed activation. Overall, this study showed suppresses through RB1-dependent RB1-independent pathways, indicating inhibition could be potential strategy overcome immunosuppression Significance: Inhibiting activates by regulating phosphorylation, suggesting combination an effective approach stimulate immunity.

Язык: Английский

Процитировано

3
When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms DOI Creative Commons

Xi-Chen Zhao,

Bo Ju,

Nuan-Nuan Xiu

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Фев. 15, 2024

Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic acute myeloid leukemia unequivocal neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs detected approximately one-third patients. In patients harboring MN-related genetic aberrations, poor response immunosuppressive therapy (IST) an increased risk transformation occurring either naturally or after IST predicted. Approximately 10%-15% with severe transform the disease phenotype following IST, some patients, leukemic emerges during shortly IST. Phenotypic transformations between AHF can occur reciprocally. A fraction advanced MN experience aplastic crisis which blasts repressed. The switch that shapes change strength extramedullary inflammation. Both have immune-active bone marrow (BM) environment (BME). inflamed BME evoked by infiltrated immune cells targeting neoplastic molecules, contributes BM-specific impairment. Autoimmune responses may represent antileukemic mechanism, inflammatory stressors strengthen immunity, at least significant proportion who aberrations. During active episodes, normal hematopoieses suppressed, leads occurrence cytopenia cell regression. successful treatment underlying infections mitigates stress-related activities promotes penetration hematopoiesis. effect similar treating infections. Investigating stress-powered immunity highly important theoretical studies clinical practice, especially given wide application immune-activating agents checkpoint inhibitors neoplasms.

Язык: Английский

Процитировано

2
STING Promotes the Progression of ADPKD by Regulating Mitochondrial Function, Inflammation, Fibrosis, and Apoptosis DOI Creative Commons
Jiao Wu, Shasha Cheng,

G.H. Lee

и другие.

Biomolecules, Год журнала: 2024, Номер 14(10), С. 1215 - 1215

Опубликована: Сен. 26, 2024

Autosomal dominant polycystic kidney disease (ADPKD) is a predominant genetic disease, which caused by mutations in PKD genes and associated with DNA damage cystic cells. The intrinsic stimulator of interferon (STING) pathway crucial for recognizing damaged the cytosol, triggering expression inflammatory cytokines to activate defense mechanisms. However, precise roles mechanisms STING ADPKD remain elusive. In this study, we show that

Язык: Английский

Процитировано

2
Recent advancements in cGAS-STING activation, tumor immune evasion, and therapeutic implications DOI
Md Saiful Islam, Mohammad Saiful Islam, Mst Rubaiat Nazneen Akhand

и другие.

Medical Oncology, Год журнала: 2024, Номер 41(11)

Опубликована: Окт. 18, 2024

Язык: Английский

Процитировано

2