An autocatalytic multicomponent DNAzyme nanomachine for tumor-specific photothermal therapy sensitization in pancreatic cancer

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 30, 2023

Multicomponent deoxyribozymes (MNAzymes) have great potential in gene therapy, but their ability to recognize disease tissue and further achieve synergistic regulation has rarely been studied. Herein, Arginylglycylaspartic acid (RGD)-modified Distearyl acylphosphatidyl ethanolamine (DSPE)-polyethylene glycol (PEG) (DSPE-PEG-RGD) micelle is prepared with a DSPE hydrophobic core load the photothermal therapy (PTT) dye IR780 calcium efflux pump inhibitor curcumin. Then, MNAzyme distributed into hydrophilic PEG layer sealed phosphate through biomineralization. Moreover, RGD attached outer tail of for tumor targeting. The constructed nanomachine can release cofactor Ca2+ under acidic conditions self-assemble an active mode cleave heat shock protein (HSP) mRNA by consuming oncogene miRNA-21. Silencing miRNA-21 enhances expression suppressor PTEN, leading PTT sensitization. Meanwhile, curcumin maintains high intracellular suppress HSP-chaperone ATP disrupting mitochondrial homeostasis. Therefore, pancreatic cancer triple-sensitized IR780-mediated PTT. vitro vivo results show that MNAzyme-based strongly regulate HSP PTEN lead significant inhibition laser irradiation.

Language: Английский

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How protons pave the way to aggressive cancers

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(12), P. 825 - 841

Published: Oct. 26, 2023

Language: Английский

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Nanomedicine Remodels Tumor Microenvironment for Solid Tumor Immunotherapy

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(15), P. 10217 - 10233

Published: April 2, 2024

Although immunotherapy is relatively effective in treating hematological malignancies, their efficacy against solid tumors still suboptimal or even noneffective presently. Compared to cancers, exhibit strikingly different immunosuppressive microenvironment, severely deteriorating the of immunotherapy: (1) chemical features such as hypoxia and mild acidity suppress activity immune cells, (2) pro-tumorigenic domestication cells microenvironment within further undermines effectiveness immunotherapy, (3) dense physical barrier tumor tissues prevents intratumoral infiltration contact killing active cells. Therefore, we believe that reversing are critical priority for tumors. Due unique morphologies, structures, compositions, nanomedicines have become powerful tools achieving this goal. In Perspective, will first briefly introduce then summarize most recent progresses nanomedicine-based by remodeling immune-microenvironment a comprehensive manner. It highly expected Perspective aid advancing tumors, optimistic on future development burgeoning field.

Language: Английский

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Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(8), P. 1206 - 1226

Published: June 6, 2024

Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA cells contributes uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y

Language: Английский

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Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115206 - 115206

Published: Jan. 1, 2025

Language: Английский

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Mechanisms of alkaliptosis

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Aug. 4, 2023

Malignant tumors represent a major threat to global health and the search for effective treatments is imperative. While various exist, including surgery, radiotherapy, chemotherapy, immunotherapy combination therapies, there remains need develop therapies that target regulated cell death pathways eliminate cancer cells while preserving normal cells. Alkaliptosis, pH-dependent process triggered by small molecular compound JTC801, has been identified as novel approach malignant tumor treatment, particularly in pancreatic cancer. Two signaling pathways, NF-κB-CA9 pathway ATP6V0D1-STAT3 pathway, contribute induction of alkaliptosis. This review summarizes recent developments our understanding alkaliptosis signals, mechanisms, modulation, explores its context-dependent effects on drug resistance, inflammation, immunity. By providing deeper heterogeneity plasticity this information holds promise informing design more anti-tumor therapies.

Language: Английский

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Acidosis-mediated increase in IFN-γ-induced PD-L1 expression on cancer cells as an immune escape mechanism in solid tumors

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Dec. 15, 2023

Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by heterogeneous and hypoxic tumor microenvironment (TME) solid tumors. In TME, programmed death-ligand 1 (PD-L1) expression on cells mainly regulated Interferon-gamma (IFN-γ), which induces T cell exhaustion enables immune evasion. this study, we demonstrate that acidosis, a common characteristic tumors, significantly increases IFN-γ-induced PD-L1 aggressive cells, thus promoting escape. Using preclinical models, found acidosis enhances genomic phosphorylation signal transducer activator transcription (STAT1), translation STAT1 mRNA eukaryotic initiation factor 4F (elF4F), resulting in an increased expression. We observed effect murine human anti-PD-L1-responsive lines, but not anti-PD-L1-nonresponsive lines. vivo studies fully validated our vitro findings revealed neutralizing acidic extracellular pH sodium bicarbonate treatment suppresses promotes infiltration responsive tumors reduces growth. However, was experiments tumor-bearing IFN-γ-/- mice dependency cell-derived IFN-γ for acidosis-mediated induction Thus, elevation represent previously unknown escape mechanism may serve as novel biomarker anti-PD-L1/PD-1 response. These important implications development new strategies to enhance immunotherapy patients.

Language: Английский

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Lactylation: The Metabolic Accomplice Shaping Cancer's Response to Radiotherapy and Immunotherapy

Ageing Research Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 102670 - 102670

Published: Jan. 1, 2025

Language: Английский

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A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours

Nature Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Abstract Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8 + cells, we identified 83 targets and applied single-cell RNA sequencing to disclose transcriptome changes associated with each perturbation the context of pancreatic cancer. This revealed elongation very long-chain fatty acids protein 1 ( Elovl1 ) as target sustain effector functions memory phenotypes cells. Accordingly, inactivation adoptively transferred cells combined anti-PD-1 showed therapeutic efficacy resistant melanoma tumours. The accumulation saturated -deficient destabilized INSIG1, leading SREBP2 activation, increased plasma membrane cholesterol stronger receptor signalling. mitochondrial fitness acid oxidation, thus withstanding stress imposed by tumour microenvironment. Finally, ELOVL1 correlated response patients melanoma. Altogether, targeting synergizes promote effective responses.

Language: Английский

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In silico analysis of the solute carrier (SLC) family in cancer indicates a link among DNA methylation, metabolic adaptation, drug response, and immune reactivity

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

Published: June 15, 2023

Introduction: The oncogenic transformation is driven by genetic and epigenetic alterations influencing cancer cell fate. These also result in metabolic reprogramming modulating the expression of membrane Solute Carrier (SLC) transporters involved biomolecules trafficking. SLCs act as tumor suppressors or promoters methylome, growth, immune-escape, chemoresistance. Methods: This silico study aimed to identify deregulated various types compared normal tissues analyzing TCGA Target GTEx dataset. Furthermore, relationship between most relevant features was tackled along with their regulation mediated DNA methylation. Results: We identified 62 differentially expressed SLCs, including downregulated SLC25A27 SLC17A7, well upregulated SLC27A2 SLC12A8. Notably, SLC4A4 SLC7A11 associated favorable unfavorable outcome, respectively. Moreover, SLC6A14, SLC34A2, SLC1A2 were linked immune responsiveness. Interestingly, SLC24A5 SLC45A2 positively correlated anti-MEK anti-RAF sensitivity. hypo- hyper-methylation promoter body region, showing an established methylation pattern. Noteworthy, positive association cg06690548 (SLC7A11) outcome suggests independent predictive role at a single nucleotide resolution. Discussion: Although our overview revealed wide heterogeneity depending on different functions types, we key pointed out regulatory mechanism expression. Overall, these findings deserve further studies novel biomarkers promising therapeutic targets.

Language: Английский

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