Tumor cell senescence-induced macrophage CD73 expression is a critical metabolic immune checkpoint in the aging tumor microenvironment

Theranostics, Год журнала: 2024, Номер 14(3), С. 1224 - 1240

Опубликована: Янв. 1, 2024

Background:The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy chemotherapy, can induce cellular senescence.Cellular interactions are widespread TME, reprogram immune metabolically by producing metabolites.However, how remodel metabolism TME remains unclear.This study aimed to explore precise targets enhance cells-induced anti-tumor immunity from a metabolic perspective. Methods:The vivo senescence model was induced 8 Gy×3 or cisplatin vitro 10 Gy-irradiation treatment.Metabonomic analysis ELISA assay on interstitial fluid were performed for metabolites screening.Marker expression cell infiltration analyzed flow cytometry.Cell co-culture system senescence-conditioned medium used crosstalk validation vitro.RNA sequencing rescue experiments conducted mechanism excavation.Immunofluorescence staining single-cell transcriptome profiling clinical validation.Results: We innovatively reveal landscape characterized with elevation adenosine.It attributed cell-induced CD73 upregulation tumor-associated macrophages (TAMs).CD73 TAMs evoked SASP-related pro-inflammatory cytokines, especially IL-6, regulated JAK/STAT3 pathway.Consistently, positive correlation between identified lung cancer specimens databases.Lastly, blocking background suppresses tumors activates CD8 + T cell-mediated antitumor immunity.Conclusions: expressed contributes significantly adenosine accumulation suggesting targeting novel synergistic strategy aging microenvironment.

Язык: Английский

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Glioma–Immune Cell Crosstalk in Tumor Progression

Cancers, Год журнала: 2024, Номер 16(2), С. 308 - 308

Опубликована: Янв. 11, 2024

Glioma progression is a complex process controlled by molecular factors that coordinate the crosstalk between tumor cells and components of microenvironment (TME). Among these, immune play critical role in cancer survival progression. The interplay TME influences outcome immunotherapy other anti-cancer therapies. Here, we present an updated view pro- anti-tumor activities main myeloid lymphocyte cell populations glioma TME. We review underlying mechanisms involved enable gliomas to evade system co-opt these for growth. Lastly, discuss current experimental therapeutic options being developed revert immunosuppressive activity Knowledge elapses may help develop new combination treatments able overcome evasion enhance response immunotherapies.

Язык: Английский

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Τ cell-mediated adaptive immunity in the transition from metabolic dysfunction-associated steatohepatitis to hepatocellular carcinoma

Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12

Опубликована: Май 7, 2024

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressed version of metabolic steatotic liver disease (MASLD) characterized by inflammation and fibrosis, but also a pathophysiological "hub" that favors emergence malignancies. Current research efforts aim to identify risk factors, discover biomarkers, aid patient stratification in context MASH-induced hepatocellular carcinoma (HCC), most prevalent cancer among MASLD patients. To investigate tumorigenic transition HCC, researchers predominantly exploit preclinical animal-based MASH models studies based on archived human biopsies clinical trials. Recapitulating immune response during tumor development progression vital obtain mechanistic insights into HCC. Notably, advanced complexity behind pathogenesis shifted focus towards innate immunity, fundamental element hepatic niche usually altered robustly course disease. During last few years, however, there has been an increasing interest for deciphering role adaptive immunity particularly regarding functions various T cell populations. effectively understand specific cells HCC development, scientists should urgently fill current knowledge gaps this field. Pinpointing signature, sketching landscape, characterizing cellular interactions dynamics within MASH-HCC are essential unravel mechanisms exploits enable cancer. end, our review aims summarize state linked

Язык: Английский

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Pyrimidine compounds BY4003 and BY4008 inhibit glioblastoma cells growth via modulating JAK3/STAT3 signaling pathway

Neurotherapeutics, Год журнала: 2024, Номер 21(5), С. e00431 - e00431

Опубликована: Авг. 16, 2024

Glioblastoma (GBM) is a brain tumor characterized by its aggressive and invasive properties. It found that STAT3 abnormally activated in GBM, inhibiting signaling can effectively suppress progression. In this study, novel pyrimidine compounds, BY4003 BY4008, were synthesized to target the JAK3/STAT3 pathway, their therapeutic efficacy mechanisms of action evaluated compared with Tofacitinib U251, A172, LN428 patient-derived glioblastoma cells. The ADP-Glo™ kinase assay was utilized assessed inhibitory effects BY4008 on JAK3, crucial member JAK family. results showed both compounds significantly inhibited JAK3 enzyme activity, IC

Язык: Английский

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Association of immunoglobulin E levels with glioma risk and survival

JNCI Journal of the National Cancer Institute, Год журнала: 2024, Номер unknown

Опубликована: Окт. 24, 2024

Previous epidemiologic studies have reported an association of serum immunoglobulin E (IgE) levels with reduced glioma risk, but the between IgE and prognosis has not been characterized. This study aimed to examine how sex, tumor subtype, class modulate risk survival.

Язык: Английский

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Targeting JAK/STAT3 in glioblastoma cells using an alginate-PNIPAm molecularly imprinted hydrogel for the sustained release of ruxolitinib

International Journal of Biological Macromolecules, Год журнала: 2025, Номер unknown, С. 140025 - 140025

Опубликована: Янв. 1, 2025

Язык: Английский

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Peptide‑based therapeutic strategies for glioma: current state and prospects

Peptides, Год журнала: 2025, Номер 185, С. 171354 - 171354

Опубликована: Фев. 6, 2025

Язык: Английский

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Targeting STAT3 for Cancer Therapy: Focusing on Y705, S727, or Dual Inhibition?

Cancers, Год журнала: 2025, Номер 17(5), С. 755 - 755

Опубликована: Фев. 23, 2025

Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that strongly implicated in various cancers. In its canonical signaling pathway, Janus kinases (JAKs) phosphorylate STAT3 at the Y705 residue response to cytokines or growth factors, with pY705 serving as key marker oncogenic activity. Elevated levels correlate poor prognosis, numerous small-molecule inhibitors have been developed block this phosphorylation site. More recently, S727 (pS727) has emerged critical contributor STAT3-mediated oncogenesis, particularly due role mitochondrial translocation. Evidence suggests pS727 may even surpass driving These findings prompt an important question: Which should be prioritized for effective inhibition cancer therapy? This review compiles critically analyzes current literature on targeting and/or pS727, evaluating their therapeutic efficacy vitro, vivo, clinical trials. We assess unique effects each downstream signaling, toxicity, outcomes. Our analysis indicates both achieve greatest effectiveness. However, associated higher toxicity risks. Comprehensive evaluation underscores importance maximum benefit. The also shows co-targeting increase overall efficacy. approached lower affinity minimize enhance feasibility dual-targeting strategies.

Язык: Английский

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Convallatoxin inhibits proliferation and angiogenesis of glioma cells via regulating JAK/STAT3 pathway

Open Life Sciences, Год журнала: 2025, Номер 20(1)

Опубликована: Янв. 1, 2025

Gliomas can cause nerve cancer-related death, and surgical removal be challenging. Convallatoxin functioned as anti-proliferation anti-angiogenesis in cancer cells. However, convallatoxin's effect on glioma remains unclear. The aim of this study is to investigate the convallatoxin proliferation angiogenesis cells, explore underlying mechanism. Human cell lines U251MG A172 were treated with 12.5, 25, 50 nM convallatoxin. Cell was investigated using CCK-8 assay colony formation assay. Migration invasion analyzed transwell assays. Angiogenesis evaluated a tube phosphorylation Janus kinase (JAK) signal transducer activator transcription 3 (STAT3) measured Western blots. A xenotransplantation model nude mice used progression. In dose-dependently reduced viability formation. suppressed migration invasion. Similarly, convallatoxin-treated cells had weakened angiogenesis. downregulated JAK STAT3 levels. also inhibited progression models. By inhibiting JAK/STAT3 signaling pathway, proliferation, migration, invasion, proving promising therapeutic candidate for gliomas.

Язык: Английский

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Stat3 Silencing Affects Circadian Clock Gene Expression and Lipopolysaccharide Response in the Suprachiasmatic Nucleus, Cortex, and Glioblastoma Cell Cultures

The FASEB Journal, Год журнала: 2025, Номер 39(10)

Опубликована: Май 12, 2025

ABSTRACT In mammals, the suprachiasmatic nucleus (SCN) serves as central circadian pacemaker, regulating rhythms essential for physiological processes. STAT3, a transcription factor primarily involved in immune signaling, exhibits rhythmicity SCN astrocytes. This study examined role of STAT3 regulation across several cell types, including primary cultures rat and cortex, cells organotypic slices from PER2::LUC mice, C6 glioblastoma cells. Furthermore, involvement inflammatory responses was investigated cortical cultures. silencing enhanced Bmal1 expression all tested disrupted cells, reduced amplitude PER2‐driven rhythm bioluminescence also attenuated its own Gfap , whereas it exhibited broader effects. Under LPS stimulation, most LPS‐induced genes, oxidative stress markers, while showing variable effects These findings indicate that clockwork appears consistent functional gene may vary depending on tissue differ between

Язык: Английский

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