Wrecking neutrophil extracellular traps and antagonizing cancer-associated neurotransmitters by interpenetrating network hydrogels prevent postsurgical cancer relapse and metastases

Bioactive Materials, Journal Year: 2024, Volume and Issue: 39, P. 14 - 24

Published: May 14, 2024

Tumor-promoting niche after incomplete surgery resection (SR) can lead to more aggressive local progression and distant metastasis with augmented angiogenesis-immunosuppressive tumor microenvironment (TME). Herein, elevated neutrophil extracellular traps (NETs) cancer-associated neurotransmitters (CANTs, e.g., catecholamines) are firstly identified as two of the dominant inducements. Further, an injectable fibrin-alginate hydrogel high tissue adhesion has been constructed specifically co-deliver NETs inhibitor (DNase I)-encapsulated PLGA nanoparticles unselective β-adrenergic receptor blocker (propranolol). The components (i.e., fibrin alginate) respond triggers (thrombin Ca2+, respectively) in postoperative bleeding gelate, shaping into interpenetrating network (IPN) featuring strength. continuous release DNase I PR wreck antagonize catecholamines decrease microvessel density, blockade myeloid-derived suppressor cells, secrete various proinflammatory cytokines, potentiate natural killer cell function hamper cytotoxic T exhaustion. reprogrammed TME significantly suppress locally residual tumors, induce strong immune memory effects thus inhibit lung metastasis. Thus, targetedly degrading blocking CANTs enabled by this in-situ IPN-based drug depot provides a simple efficient approach against SR-induced cancer recurrence

Language: Английский

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Neutrophil extracellular traps promote growth of lung adenocarcinoma by mediating the stability of m6A‐mediated SLC2A3 mRNA‐induced ferroptosis resistance and CD8(+) T cell inhibition

Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(2)

Published: Jan. 26, 2025

Abstract To investigate the potential mechanisms underlying neutrophil extracellular traps (NETs) confer ferroptosis resistance and CD8(+) T cell inhibition in lung adenocarcinoma (LUAD). By intravenous injection of LLC cells into tail vein, a LUAD mouse model was created. Phorbol‐12‐myristate‐13‐acetate (PMA) stimulated neutrophils to facilitate NETs formation combined with inhibitor DNase I explore mechanism on proliferation, migration, resistance, activity. CitH3, myeloperoxidase (MPO), cell‐free DNA, MPO‐DNA levels were increased, indicating an increase LUAD. PMA promoted tumours mice, increased number CD3(+)CD4(+) cells, decreased perforin, granzyme A, B, IFNγ, TNF‐α levels, growth tumour nodules, that formation, reduced activity CD8(+)T growth. partially reversed effects PMA. proliferation while effects. Erastin inhibited migration ferroptosis. Further results showed by promoting YTHDF2‐mediated SLC2A3 mRNA degradation. Sh‐YTHDF2 effect whereas si‐SLC2A3 sh‐YTHDF2 cells. In addition, inhibiting tumours, Our suggested through

Language: Английский

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Tumor-Associated Neutrophils in Colorectal Cancer Development, Progression and Immunotherapy

Cancers, Journal Year: 2022, Volume and Issue: 14(19), P. 4755 - 4755

Published: Sept. 29, 2022

The colorectal-cancer (CRC) incidence rate and mortality have remained high for several years. In recent years, immune-checkpoint-inhibitor (ICI) therapy has rapidly developed. However, it is only effective in a few CRC patients with microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) CRC. How to improve the efficiency of ICI microsatellite stability (MSS) remains huge obstacle. Tumor-associated neutrophils (TANs), which are similar macrophages, also N1 N2 phenotypes. They can be recruited polarized through different cytokines chemokines, then play an antitumor tumor-promoting role. CRC, we find that prognostic significance TANs still controversial. this review, describe regulation TANs, their mechanism promoting tumor progression by boosting transformation inflammation into tumors, facilitating tumor-cell proliferation, metastasis angiogenesis. targeting combined ICIs may new treatment model Relevant animal experiments shown good responses, clinical trials been carried out succession. as “assistants” treatment, become key success immunotherapy, although no significant results obtained.

Language: Английский

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Identification of NETs-related biomarkers and molecular clusters in systemic lupus erythematosus

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: April 18, 2023

Neutrophil extracellular traps (NETs) is an important process involved in the pathogenesis of systemic lupus erythematosus (SLE), but potential mechanisms NETs contributing to SLE at genetic level have not been clearly investigated. This investigation aimed explore molecular characteristics NETs-related genes (NRGs) based on bioinformatics analysis, and identify associated reliable biomarkers clusters. Dataset GSE45291 was acquired from Gene Expression Omnibus repository used as a training set for subsequent analysis. A total 1006 differentially expressed (DEGs) were obtained, most which with multiple viral infections. The interaction DEGs NRGs revealed 8 (DE-NRGs). correlation protein-protein analyses these DE-NRGs performed. Among them, HMGB1, ITGB2, CREB5 selected hub by random forest, support vector machine, least absolute shrinkage selection operator algorithms. significant diagnostic value confirmed three validation sets (GSE81622, GSE61635, GSE122459). Additionally, sub-clusters identified genes' expression profiles analyzed unsupervised consensus cluster assessment. Functional enrichment performed among subgroups, data that 1 highly prevalent innate immune response pathways while 3 enriched adaptive pathways. Moreover, infiltration analysis also cells markedly infiltrated upregulated 3. As per our knowledge, this first SLE, (HMGB1, CREB5), distinct clusters biomarkers.

Language: Английский

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Identifying neutrophil-associated subtypes in ulcerative colitis and confirming neutrophils promote colitis-associated colorectal cancer

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 10, 2023

Background Ulcerative colitis (UC) is a chronic inflammatory disease of the intestinal mucosa, incidence which has increased worldwide. There still lack clear understanding pathogenesis ulcerative that ultimately leads to colitis-associated colorectal cancer. Method We download UC transcriptome data from GEO database and pass limma package in order identify differentially expressed genes. Gene Set Enrichment Analysis (GSEA) was used potential biological pathways. identified immune cells associated with by CIBERSORT Weighted co-expression network analysis (WGCNA). validation cohorts mouse models verify expression hub genes role neutrophils. Result 65 samples healthy controls. GSEA, KEGG, GO analyses displayed DEGs were enriched immune-related revealed infiltration neutrophils tissues. The red module, obtained WGCNA analysis, considered be most relevant module for neutrophils.Based on neutrophil-associated genes, patients classified into two subtypes neutrophil infiltration. discovered highly neutrophil-infiltrated subtype B had higher risk developing CAC. Five as biomarkers searching between distinct subtypes. Finally, using model, we determined these five control, DSS, AOM/DSS groups. degree mice percentage MPO pSTAT3 analyzed flow cytometry. In expressions significantly increased. Conclusions These findings suggested might promote conversion improve our CAC provide new more effective insights prevention treatment

Language: Английский

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The lipid-metabolism enzyme ECI2 reduces neutrophil extracellular traps formation for colorectal cancer suppression

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

Published: Aug. 21, 2024

Abnormalities in ether lipid metabolism as well the formation of neutrophil extracellular traps have recently been recognized detrimental factors affecting tumorigenesis and progression. However, role abnormal colorectal cancer (CRC) evolution has not reported. Here we show that metabolism-related gene enoyl-CoA δ-isomerase 2 (ECI2) plays a tumor-suppressor CRC is negatively associated with poor prognosis patients. We mechanistically demonstrate ECI2 reduces lipid-mediated Interleukin 8 (IL-8) expression leading to decreased recruitment for suppression. In particular, inhibits production cells by inhibiting peroxisomal localization alkylglycerone phosphate synthase (AGPS), rate-limiting enzyme synthesis. These findings only deepen our understanding metabolic reprogramming interactions progression CRC, but also provide ideas identifying potential diagnostic markers therapeutic targets CRC. The association between rewiring tumour microenvironment shown be relevant Here, authors ether-lipid generation

Language: Английский

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Mucous Permeable Nanoparticle for Inducing Cuproptosis‐Like Death In Broad‐Spectrum Bacteria for Nebulized Treatment of Acute Pneumonia

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Abstract The emergence of antibiotic‐resistant bacteria has exacerbated the challenge treating infectious diseases. Quorum sensing (QS), a bacterial communication system regulating virulence and biofilm formation, presents target for novel therapies. Cuproptosis death is innovation mode death, however, this effect may be partially inhibited by glutathione (GSH). Buthionine sulfoximine (BSO) responsible GSH biosynthesis been identified as potential promoter cuproptosis death. Here, Cu 2 O‐BSO NPs with lung adhesion mucus penetration ability are synthesized incorporating BSO onto O, modifying it DOPA PEG. demonstrated broad‐spectrum antibacterial activity against both Gram‐positive Gram‐negative bacteria, making viable treatment option MRSA‐induced acute pneumonia. Specifically, can synergistically enhance cuproptosis‐like hinder QS system, eradicate biofilms, reduce strains, stimulate chemotaxis phagocytosis macrophages, ultimately improve in mice severe This research wide‐ranging alternative, providing promise addressing microbial resistance combatting formation. Additionally, established theoretical foundation clinical numerous challenging cases drug‐resistant bacteria.

Language: Английский

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A novel neutrophil extracellular trap signature to predict prognosis and immunotherapy response in head and neck squamous cell carcinoma

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 23, 2022

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant cancers, patients with HNSCC possess early metastases poor prognosis. Systematic therapies (including chemotherapy, targeted therapy, immunotherapy) are generally applied in advanced/late stages HNSCC, but primary acquired resistance eventually occurs. At present, reliable biomarkers to predict prognosis have not been completely identified. Recent studies shown that neutrophil extracellular traps (NETs) implicated cancer progression, metastasis immune response, NET-related gene signatures associated several human cancers. To explore whether genes play crucial roles we performed systematic analysis reported findings current study. Firstly, identified seven novel developed a NET-score signature, which was highly clinicopathological traits patients. Then, we, for first time, found NIFK significantly upregulated patient samples, its levels were linked tumor malignancy status. Moreover, functional experiments confirmed required proliferation metastasis. Altogether, this study has signature based on also explored new method personalized chemo-/immuno-therapy HNSCC.

Language: Английский

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Noninvasive evaluation of neutrophil extracellular traps signature predicts clinical outcomes and immunotherapy response in hepatocellular carcinoma

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: July 13, 2023

Background Neutrophil extracellular traps (NETs) have been shown to play a pivotal role in promoting metastasis and immune escape hepatocellular carcinoma (HCC). Therefore, noninvasive tests detect the formation of NETs tumors can significant implications for treatment prognoses patients. Here, we sought develop validate computed tomography (CT)-based radiomics model predict gene expression profiles that regulate HCC. Methods This study included 1133 HCC patients from five retrospective cohorts. Based on mRNA levels 69 biomarkers correlated with NET formation, 6-gene score (NETs score, NETS) was constructed cohort 1 TCIA database (n=52) validated 2 (n=232) ICGC 3 (n=365) TCGA database. And then based features CT images, signature (RNETS) developed NETS status (high- or low-NETS). We further employed two cohorts Nanfang Hospital (Guangzhou, China) evaluate predictive power RNETS predicting prognosis 4 (n=347) responses PD-1 inhibitor 5 (n=137). Results For NETS, 1, area under curve (AUC) values 2, 3-year overall survival (OS) were 0.836, 0.879, 0.902, respectively. The low-NETS associated better higher cell infiltration. yielded an AUC value 0.853 distinguishing between high-NETS low-RNETS significantly longer time ( P <0.001). Notably, competent disease-free (DFS) OS In 5, found be independent risk factor progression-free (PFS) addition, objective response rate treated group (27.8%) than high-RNETS (10.8%). Conclusions revealed as biomarker could effectively immunotherapy

Language: Английский

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An Inflammatory Checkpoint Generated by IL1RN Splicing Offers Therapeutic Opportunity for KRAS-Mutant Intrahepatic Cholangiocarcinoma

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(10), P. 2248 - 2269

Published: July 24, 2023

KRAS mutations are causally linked to protumor inflammation and identified as driving factors in tumorigenesis. Here, using multiomics data gathered from a large set of patients, we showed that mutation was associated with specific landscape alternative mRNA splicing connected myeloid intrahepatic cholangiocarcinoma (iCCA). Then, negative feedback mechanism which the upregulation interleukin 1 receptor antagonist (IL1RN)-201/203 due confers vital anti-inflammatory effects KRAS-mutant iCCA. In iCCA mice, both IL1RN-201/203 anakinra treatment ignited significant antitumor immune response by altering neutrophil recruitment phenotypes. Furthermore, synergistically enhanced anti-PD-1 therapy activate intratumoral GZMB+ CD8+ T cells mice. Clinically, found high levels patients were significantly superior immunotherapy. This work describes novel inflammatory checkpoint mediated IL1RN variants may serve promising basis develop therapeutic options for other cancers. article is featured Selected Articles Issue, p. 2109.

Language: Английский

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