The Exonuclease TREX1 Constitutes an Innate Immune Checkpoint Limiting cGAS/STING-Mediated Antitumor Immunity DOI Creative Commons
J. K. Lim, Ryan Rodriguez, Katherine Williams

et al.

Cancer Immunology Research, Journal Year: 2024, Volume and Issue: 12(6), P. 663 - 672

Published: March 15, 2024

Abstract The DNA exonuclease three-prime repair 1 (TREX1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to production type I IFNs. As tumor cells are prone aberrant accumulation, we hypothesized that they critically dependent on TREX1 activity limit their immunogenicity. Here, show cells, restricts spontaneous pathway, subsequent induction a IFN response. result, deficiency compromised vivo growth mice. This delay depended functional immune system, systemic signaling, tumor-intrinsic cGAS expression. Mechanistically, loss drove CD8+ T NK prevented T-cell exhaustion, remodeled an immunosuppressive myeloid compartment. Consequently, combined with T-cell–directed checkpoint blockade. Collectively, conclude essential immunogenicity, targeting this remodels microenvironment enhances antitumor immunity itself combination T-cell–targeted therapies. See related article Toufektchan et al., p. 673

Language: Английский

RNAi-based drug design: considerations and future directions DOI
Qi Tang, Anastasia Khvorova

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(5), P. 341 - 364

Published: April 3, 2024

Language: Английский

Citations

73
Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation DOI Creative Commons
Wei Xiang, Hongwei Lv, Fuxue Xing

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(49)

Published: Dec. 6, 2023

Adenosine 5'-triphosphate citrate lyase (ACLY) is a cytosolic enzyme that converts into acetyl-coenzyme A for fatty acid and cholesterol biosynthesis. ACLY up-regulated or activated in many cancers, targeting by inhibitors holds promise as potential cancer therapy. However, the role of immunity regulation remains poorly understood. Here, we show inhibition up-regulates PD-L1 immune checkpoint expression cells induces T cell dysfunction to drive immunosuppression compromise its antitumor effect immunocompetent mice. Mechanistically, causes polyunsaturated (PUFA) peroxidation mitochondrial damage, which triggers DNA leakage activate cGAS-STING innate pathway. Pharmacological genetic overcomes resistance anti-PD-L1 therapy cGAS-dependent manner. Furthermore, dietary PUFA supplementation mirrors enhanced efficacy blockade inhibition. These findings reveal an immunomodulatory provide combinatorial strategies overcome immunotherapy tumors.

Language: Английский

Citations

52
The two sides of chromosomal instability: drivers and brakes in cancer DOI Creative Commons
Rendy Hosea,

Sharon Hillary,

S. Hassan R. Naqvi

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 29, 2024

Abstract Chromosomal instability (CIN) is a hallmark of cancer and associated with tumor cell malignancy. CIN triggers chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes chromosomes. arises errors DNA replication segregation during division, formation abnormal and/or structure Errors result licensing as well stress, such double-strand breaks stalled forks; meanwhile, stem defects machinery, centrosome amplification, erroneous microtubule–kinetochore attachments, spindle assembly checkpoint, defective sister chromatids cohesion. In cells, deleterious damage, proteotoxic metabolic alteration, cycle arrest, senescence. Paradoxically, despite these negative consequences, one hallmarks found over 90% solid tumors blood cancers. Furthermore, could endow enhanced adaptation capabilities due increased intratumor heterogeneity, thereby facilitating adaptive resistance therapies; however, excessive induce death, “just-right” model for tumors. Elucidating complex nature crucial understanding dynamics tumorigenesis developing effective anti-tumor treatments. This review provides an overview causes consequences CIN, paradox phenomenon that continues perplex researchers. Finally, this explores potential CIN-based therapy.

Language: Английский

Citations

43
Cold and hot tumors: from molecular mechanisms to targeted therapy DOI Creative Commons
Bo Wu, Bo Zhang, Bowen Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 18, 2024

Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment therapy, only a minority patients exhibit positive response to it. In with solid tumors, those who respond well typically demonstrate an active profile referred as "hot" (immune-inflamed) phenotype. On other hand, non-responsive may distinct "cold" (immune-desert) phenotype, differing from features tumors. Additionally, there is more nuanced "excluded" positioned between and categories, known type. Effective differentiation understanding intrinsic factors, characteristics, TME, external factors are critical for predicting results. It widely accepted that therapy exerts profound effect on limited efficacy against or "altered" necessitating combinations therapeutic modalities enhance cell infiltration into tissue convert tumors ones. Therefore, aligning traits this review systematically delineates respective influencing extensively discusses varied approaches drug targets based assess efficacy.

Language: Английский

Citations

39
An Immunocompetent Hafnium Oxide-Based STING Nanoagonist for Cancer Radio-immunotherapy DOI
Yuhua Cao, Shuaishuai Ding,

Yunping Hu

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(5), P. 4189 - 4204

Published: Jan. 9, 2024

cGAS-STING signaling plays a critical role in radiotherapy (RT)-mediated immunomodulation. However, RT alone is insufficient to sustain STING activation tumors under safe X-ray dose. Here, we propose radiosensitization cooperated with cGAS stimulation strategy by engineering core–shell structured nanosized radiosensitizer-based agonist, which constituted the hafnium oxide (HfO2) core and manganese (MnO2) shell. HfO2-mediated enhances immunogenic cell death afford tumor associated antigens adequate cytosolic dsDNA, while GSH-degradable MnO2 sustainably releases Mn2+ improve recognition sensitization of cGAS. The synchronization sustained supply cumulative dsDNA damage synergistically augments irradiated tumors, thereby enhancing RT-triggered local system effects when combined an immune checkpoint inhibitor. Therefore, synchronous demonstrated as potent immunostimulation optimize cancer radio-immuotherapy.

Language: Английский

Citations

30
cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation DOI Creative Commons
Jingwen Liu, Jing Zhou,

Yuling Luan

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 9, 2024

Abstract Background Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression organ degeneration, but the mechanism regulation of crosstalk network remain unclear. Main body abstract Cellular stress disrupts mitochondrial homeostasis, facilitates opening permeability transition pore leakage DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, subsequently induces activation onset pyroptosis. Meanwhile, inflammasome-associated protein caspase-1, Gasdermin D, CARD domain ASC potassium channel are involved in regulating pathway. Importantly, this has a cascade amplification effect that exacerbates immuno-inflammatory response, worsening pathological process autoimmune diseases. Given importance innate immunity, it is emerging new avenue explore mechanisms multiple disease pathogenesis. Therefore, efforts define strategies selectively modulate different settings have been or ongoing. In review, we will describe how mechanistic understanding driving possible therapeutics targeting network, focusing on interacting regulatory proteins, pathways, hub between inflammasomes, Short conclusion This review aims provide insight into roles pyroptosis, highlight some promising directions future research intervention.

Language: Английский

Citations

28
Micronuclei induced by radiation, replication stress, or chromosome segregation errors do not activate cGAS-STING DOI Creative Commons

Tohru Takaki,

Rhona Millar,

Crispin T. Hiley

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(11), P. 2203 - 2213.e5

Published: May 14, 2024

The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in innate immune responses to viral infection and inhibition autoimmunity. Recent studies have suggested that micronuclei formed by genotoxic stress can activate signaling via the cGAS-STING pathway. Here, we investigated cGAS localization, activation, downstream from induced ionizing radiation, replication stress, chromosome segregation errors. Although localized ruptured binding self-DNA, failed observe activation; cGAMP production; phosphorylation STING, TBK1, or IRF3; nuclear accumulation expression interferon-stimulated genes. Failure was observed across primary immortalized cell lines, which retained ability response dsDNA modified vaccinia virus infection. We provide evidence insults contain histone-bound show is inhibitory activation cells.

Language: Английский

Citations

23
Immunotherapy for glioblastoma: current state, challenges, and future perspectives DOI Creative Commons
Yang Liu, Zhou Fei, Heba Ali

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(12), P. 1354 - 1375

Published: Oct. 15, 2024

Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard care offers minimal clinical benefit, most GBM patients experience recurrence after treatment. In recent years, significant advancements have been made the development novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance many advanced cancers. However, benefit immune-based treatments limited because unique immune profiles, cell heterogeneity, immunosuppressive microenvironment. this review, we present a detailed overview current immunotherapeutic discuss challenges potential molecular mechanisms underlying GBM. Furthermore, provide in-depth discussion regarding GBM, which will likely require combination therapies.

Language: Английский

Citations

22
cGAS-STING pathway mediates activation of dendritic cell sensing of immunogenic tumors DOI Creative Commons

Guohao Li,

Xiangqian Zhao,

Zuda Zheng

et al.

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: March 21, 2024

Abstract Type I interferons (IFN-I) play pivotal roles in tumor therapy for three decades, underscoring the critical importance of maintaining integrity IFN-1 signaling pathway radiotherapy, chemotherapy, targeted therapy, and immunotherapy. However, specific mechanism by which IFN-I contributes to these therapies, particularly terms activating dendritic cells (DCs), remains unclear. Based on recent studies, aberrant DNA cytoplasm activates cyclic GMP-AMP synthase (cGAS)- stimulator interferon genes (STING) pathway, turn produces IFN-I, is essential antiviral anticancer immunity. Notably, STING can also enhance immunity promoting autophagy, inflammation, glycolysis an IFN-I-independent manner. These research advancements contribute our comprehension distinctions between drugs agonists context oncology shed light challenges involved developing agonist drugs. Thus, we aimed summarize novel mechanisms underlying cGAS-STING-IFN-I signal activation DC-mediated antigen presentation its role cancer immune cycle this review.

Language: Английский

Citations

19
Polystyrene microplastics induce pulmonary fibrosis by promoting alveolar epithelial cell ferroptosis through cGAS/STING signaling DOI Creative Commons

Jinming Zhang,

Jiangzhou Du,

Dongyu Liu

et al.

Ecotoxicology and Environmental Safety, Journal Year: 2024, Volume and Issue: 277, P. 116357 - 116357

Published: April 26, 2024

Polystyrene microplastics (PS-MPs) are new types of environmental pollutant that have garnered significant attention in recent years since they were found to cause damage the human respiratory system when inhaled. The pulmonary fibrosis is one serious consequences PS-MPs inhalation. However, impact and underlying mechanisms on not clear. In this study, we studied potential lung toxicity PS-MPs-developed by long-term intranasal inhalation PS-MPs. results showed after exposing PS-MPs, lungs model mouse had different levels fibrosis. Meanwhile, resulted a markedly decrease glutathione (GSH), an increase malondialdehyde (MDA), iron overload tissue mice alveolar epithelial cells (AECs). These findings suggested occurrence PS-MP-induced ferroptosis. Inhibitor ferroptosis (Fer-1) alleviated PS-MPs-induced Mechanically, triggered cell promoted development via activating cGAS/STING signaling pathway. Inhibition with G150/H151 attenuated exposure. Together, these data provided novel mechanistic insights therapeutic paradigm.

Language: Английский

Citations

18