Cold and hot tumors: from molecular mechanisms to targeted therapy

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Окт. 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.

Язык: Английский

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When DNA-damage responses meet innate and adaptive immunity

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Апрель 17, 2024

Abstract When cells proliferate, stress on DNA replication or exposure to endogenous external insults frequently results in damage. DNA-Damage Response (DDR) networks are complex signaling pathways used by multicellular organisms prevent Depending the type of broken DNA, various pathways, Base-Excision Repair (BER), Nucleotide Excision (NER), Mismatch (MMR), Homologous Recombination (HR), Non-Homologous End-Joining (NHEJ), Interstrand Crosslink (ICL) repair, and other direct repair can be activated separately combination To preserve homeostasis, innate adaptive immune responses effective defenses against mutation invasion pathogens. It is interesting note that new research keeps showing how closely DDR components system related. immunological response linked effectors such as cyclic GMP-AMP synthase (cGAS)–Stimulator Interferon Genes (STING) pathway. These act sensors damage-caused response. Furthermore, themselves function trigger generation inflammatory cytokines a cascade even programmed cell death. Defective known disrupt genomic stability compromise responses, aggravating imbalance leading serious diseases cancer autoimmune disorders. This study examines most recent developments interaction between elements responses. The network’s modulators’ dual roles may offer perspectives treating infectious disorders damage, including cancer, development target immunotherapy.

Язык: Английский

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Oxidized mitochondrial DNA activates the cGAS-STING pathway in the neuronal intrinsic immune system after brain ischemia-reperfusion injury

Neurotherapeutics, Год журнала: 2024, Номер 21(4), С. e00368 - e00368

Опубликована: Апрель 30, 2024

In the context of stroke and revascularization therapy, brain ischemia-reperfusion injury is a significant challenge that leads to oxidative stress inflammation. Central cell's intrinsic immunity cGAS-STING pathway, which typically activated by unusual DNA structures. The involvement oxidized mitochondrial (ox-mtDNA)-an byproduct-in this type neurological damage has not been fully explored. This study among first examine effect ox-mtDNA on innate neurons following injury. Using rat model transient middle cerebral artery occlusion cellular oxygen-glucose deprivation/reoxygenation, we have discovered activates pathway in neurons. Importantly, pharmacologically limiting release into cytoplasm reduces inflammation improves functions. Our findings suggest targeting may be valuable strategy attenuate therapy for acute ischemic stroke.

Язык: Английский

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DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T‐cell immunity

The EMBO Journal, Год журнала: 2023, Номер 42(8)

Опубликована: Март 13, 2023

Abstract The immunoproteasome is a specialized type of proteasome involved in MHC class I antigen presentation, antiviral adaptive immunity, autoimmunity, and also part broader response to stress. Whether the regulated by DNA stress, however, not known. We here demonstrate that mitochondrial stress upregulates presentation pathway via cGAS/STING/type interferon signaling resulting cell autonomous activation CD8 + T cells. cGAS/STING‐induced immune observed genomic conserved epithelial mesenchymal cells mice men. In patients with idiopathic pulmonary fibrosis, chronic aberrant lung concurs T‐cell diseased lungs. Genetic depletion specific inhibitors counteract induced cytotoxic activation. Our data thus unravel cytoplasmic sensing cGAS/STING as an activator This represents novel potential pathomechanism for fibrosis opens new therapeutic perspectives.

Язык: Английский

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STING in Cancer Immunoediting: Modeling Tumor-Immune Dynamics Throughout Cancer Development

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

Опубликована: Янв. 16, 2025

Язык: Английский

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Antiviral CD8⁺T-cell immune responses are impaired by cigarette smoke and in COPD

European Respiratory Journal, Год журнала: 2023, Номер 62(2), С. 2201374 - 2201374

Опубликована: Июнь 29, 2023

Background Virus infections drive COPD exacerbations and progression. Antiviral immunity centres on the activation of virus-specific CD8 + T-cells by viral epitopes presented major histocompatibility complex (MHC) class I molecules infected cells. These are generated immunoproteasome, a specialised intracellular protein degradation machine, which is induced antiviral cytokines in Methods We analysed effects cigarette smoke cytokine- virus-mediated induction immunoproteasome vitro , ex vivo using RNA Western blot analyses. T-cell was determined co-culture assays with smoke-exposed influenza A virus (IAV)-infected Mass-spectrometry-based analysis MHC I-bound peptides uncovered inflammatory antigen presentation lung IAV-specific numbers were patients’ peripheral blood tetramer technology. Results Cigarette impaired cytokine signalling infection cells . In addition, altered peptide repertoire antigens under conditions. Importantly, I-mediated dampened smoke. patients exhibited reduced circulating compared to healthy controls asthmatics. Conclusion Our data indicate that interferes generation thereby contributes upon infection. This adds important mechanistic insight how mediates increased susceptibility smokers infections.

Язык: Английский

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Beyond DNA sensing: expanding the role of cGAS/STING in immunity and diseases

Archives of Pharmacal Research, Год журнала: 2023, Номер 46(6), С. 500 - 534

Опубликована: Июнь 1, 2023

Abstract Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is a DNA sensor that elicits robust type I interferon response by recognizing ubiquitous danger-associated molecules. The cGAS/stimulator of genes (cGAS/STING) activated endogenous DNA, including released from mitochondria and extranuclear chromatin, as well exogenous derived pathogenic microorganisms. cGAS/STING positioned key axis autoimmunity, the inflammatory response, cancer progression, suggesting signaling pathway represents an efficient therapeutic target. Based on accumulated evidence, we present insights into prevention treatment cGAS/STING-related chronic immune diseases. This review presents current state clinical nonclinical development modulators targeting cGAS/STING, providing useful information design strategies.

Язык: Английский

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The interplay between autophagy and cGAS-STING signaling and its implications for cancer

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Апрель 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

Язык: Английский

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Pulmonary fibrosis: pathogenesis and therapeutic strategies

MedComm, Год журнала: 2024, Номер 5(10)

Опубликована: Сен. 23, 2024

Abstract Pulmonary fibrosis (PF) is a chronic and progressive lung disease characterized by extensive alterations of cellular fate function excessive accumulation extracellular matrix, leading to tissue scarring impaired respiratory function. Although our understanding its pathogenesis has increased, effective treatments remain scarce, fibrotic progression major cause mortality. Recent research identified various etiological factors, including genetic predispositions, environmental exposures, lifestyle which contribute the onset PF. Nonetheless, precise mechanisms these factors interact drive are not yet fully elucidated. This review thoroughly examines diverse molecular mechanisms, key signaling pathways involved in PF, such as TGF‐β, WNT/β‐catenin, PI3K/Akt/mTOR. It also discusses current therapeutic strategies, antifibrotic agents like pirfenidone nintedanib, explores emerging targeting senescence. Emphasizing need for omni‐target approaches overcome limitations therapies, this integrates recent findings enhance PF development more prevention management ultimately improving patient outcomes.

Язык: Английский

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Macrophage STING signaling promotes fibrosis in benign airway stenosis via an IL6-STAT3 pathway

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 3, 2025

Acute and chronic inflammation are important pathologies of benign airway stenosis (BAS) fibrosis, which is a frequent complication critically ill patients. cGAS-STING signalling has an role in yet the function STING BAS remains unclear. Here we demonstrate using scRNA sequencing that cGAS‒STING involved BAS, accompanied by increased dsDNA, expression activation STING. inhibition or deficiency effectively alleviates tracheal fibrosis mice decreasing both acute inflammation. Macrophage depletion also ameliorates BAS. Mechanistically, dsDNA from damaged epithelial cells activates pathway macrophages induces IL-6 to activate STAT3 promote fibrosis. In summary, present results suggest amplifies associated with stenosis, highlighting mechanism potential drug target Benign characterised trachea. authors examine mouse models show involvement macrophage ameliorated

Язык: Английский

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