Prognostic models of immune-related cell death and stress unveil mechanisms driving macrophage phenotypic evolution in colorectal cancer

Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 28, 2025

Tumor microenvironment (TME), particularly immune cell infiltration, programmed death (PCD) and stress, has increasingly become a focal point in colorectal cancer (CRC) treatment. Uncovering the intricate crosstalk between these factors can enhance our understanding of CRC, guide therapeutic strategies, improve patient prognosis. We constructed an immune-related stress (ICDS) prognostic model utilizing machine learning methodologies. Furthermore, we performed enrichment analyses deconvolution algorithms to elucidate complex interactions infiltration processes PCD within substantial array transcriptomic data from The Cancer Genome Atlas (TCGA) Gene Expression Omnibus base (GEO) related CRC. Single-cell sequencing biochemical experiments were used validate interaction genes tumor cells. ICDS exhibited robust predictive performance seven independent cohorts, revealing inverse correlation scores Meanwhile, index was positively correlated with clinical stage. Model analysis indicated that subgroups low heightened activation features elevated activity pathways. further revealed macrophages central drivers characteristics underlying differences model. Pseudotime cellular gene GAL3ST4 promotes transition toward M2 pro-tumor phenotype. communication experimental validation cuproptosis cells suppress expression, thereby inhibiting M2-like macrophage polarization. In summary, uncovered mechanism by which downregulate expression via inhibit polarization, providing new targets biomarkers for CRC treatment prognosis evaluation.

Язык: Английский

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DNA Tetrahedron-Driven Multivalent Proteolysis-Targeting Chimeras: Enhancing Protein Degradation Efficiency and Tumor Targeting

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Proteolysis-targeting chimeras (PROTACs) are dual-functional molecules composed of a protein interest (POI) ligand and an E3 ligase connected by linker, which can recruit POI ligases simultaneously, thereby inducing the degradation showing great potential in disease treatment. A challenge developing PROTACs is design linkers modification ligands to establish multifunctional platform that enhances efficiency antitumor activity. As programmable modifiable nanomaterial, DNA tetrahedron precisely assemble selectively recognize flexibly adjust distance between molecules, making them ideal linkers. Herein, we developed multivalent PROTAC based on tetrahedron, named AS-TD2-PRO. Using as combined modules targeting tumor cells, recognizing ligases, multiple together. We took undruggable target signal transducer activator transcription 3 (STAT3), associated with etiology progression variety malignant tumors, example this study. AS-TD2-PRO two STAT3 recognition demonstrated good enhancing tumor-specific compared traditional bivalent PROTACs. Furthermore, mouse model, superior therapeutic activity was observed. Overall, tetrahedron-driven both serve proof principle for introduce promising avenue cancer treatment strategies.

Язык: Английский

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JTC801 regresses uveal melanoma progression through novel methuosis-like cell death via lysosomal dysfunction

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Фев. 4, 2025

Uveal melanoma (UM) is the most frequent primary intraocular malignancy in adults with high metastasis and mortality rate, whose effective therapeutic strategy still urgent need. Specifically, apoptosis-resistance a great challenge for advanced UM patients, therefore novel options targeting otherwise death modality, which may potentially enhance treatment effect, need to be further identified. Here, by kinase inhibitor library of 113 approved drugs screening, JTC801, selective antagonist nociceptin receptor (NOP), exhibits specifically strong tumor-killing ability lower dosage. JTC801 induces cell methuosis-like characterized cytoplasmic vacuolization, markedly regresses tumor progression metastasis, prolongs survival multiple models without apparent adverse effects. Mechanistically, JTC801-caused nutrient-deficient stress mitochondrial damage triggers macropinocytosis vacuolization cells. Concomitantly, trapped into macropinosomes that fuse lysosomes, causing lysosomal over-acidification, de-glycosylation associated membrane protein 1(LAMP1), inhibiting cathepsinsmaturation, exacerbating permeabilization (LMP), eventually inducing death. Collectively, our findings identify as potential valuable antitumor drug especially apoptosis-resistant provide insight distinct cytotoxicity role treatment.

Язык: Английский

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Glucose Metabolism‐Targeted Poly(amino acid) Nanoformulation of Oxaliplatin(IV)‐Aspirin Prodrug for Enhanced Chemo‐Immunotherapy

Advanced Materials, Год журнала: 2025, Номер unknown

Опубликована: Фев. 14, 2025

Inappropriate glucose metabolism in cancer cells is associated with immunosuppressive tumor microenvironments (TMEs). Although glycolysis inhibition enhances T cell-mediated immune responses, the integrated platforms combining immunotherapy remain underdeveloped. To address this gap, a metabolism-targeted poly(amino acid) nanoformulation of oxaliplatin(IV)-aspirin prodrug (NP/OXA-ASP2) developed to improve chemo-immunotherapy by suppressing glycolysis. This nanoparticle exhibits selective release, discharging 90.0% OXA-ASP2 under reductive conditions within 36 h. Furthermore, over 80% converts OXA and ASP 12 h, promoting mitochondrial damage inhibition, which amplifies immunogenic cell death induced OXA. In addition, glycolytic flux reduces lactate leakage, mitigating TMEs. Together, these mechanisms contribute stronger efficacy. Compared plus formulation, NP/OXA-ASP2 demonstrates superior performances, reducing levels at site 25.4%, increasing proportion cytotoxic lymphocytes 1.53 times, decreasing regulatory 2.20 improving 1.39-fold rate. These findings underscore that promising platform for integrating metabolic regulation immunomodulation holds significant potential advancing clinical chemo-immunotherapy.

Язык: Английский

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Dying to survive: harnessing inflammatory cell death for better immunotherapy

Trends in cancer, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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RIPK1 is required for ZBP1-driven necroptosis in human cells

PLoS Biology, Год журнала: 2025, Номер 23(2), С. e3002845 - e3002845

Опубликована: Фев. 21, 2025

Necroptosis initiated by the host sensor Z-NA binding protein 1 (ZBP1) is essential for defense against a growing number of viruses, including herpes simplex virus (HSV-1). Studies with HSV-1 and other necroptogenic stimuli in murine settings have suggested that ZBP1 triggers necroptosis directly complexing kinase RIPK3. Whether this also case human cells, or whether additional co-factors are needed ZBP1-mediated necroptosis, unclear. Here, we show ZBP1-induced cells requires RIPK1. We found RIPK1 forming stable functional ZBP1-RIPK3 complex but dispensable formation equivalent complex. The receptor-interacting (RIP) homology interaction motif (RHIM) RIPK3 responsible difference between 2 species, because replacing RHIM from sufficient to overcome requirement cells. These observations describe critical mechanistic mice humans how engages important implications treating diseases.

Язык: Английский

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RIPK3 in Necroptosis and Cancer

Molecules and Cells, Год журнала: 2025, Номер unknown, С. 100199 - 100199

Опубликована: Фев. 1, 2025

Язык: Английский

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Design, synthesis, and biological evaluation of RIPK1-targeting PROTACs

Molecular Diversity, Год журнала: 2025, Номер unknown

Опубликована: Март 24, 2025

Язык: Английский

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Oligomerised RIPK1 is the main core component of the CD95 necrosome

The EMBO Journal, Год журнала: 2025, Номер unknown

Опубликована: Апрель 16, 2025

Abstract The necrosome is the key macromolecular signaling platform initiating necroptosis, i.e., a RIPK1/RIPK3-dependent program of cell death with an important role in control inflammation multicellular organisms. However, composition and structure remain incompletely understood. Here we use biochemical assays, quantitative mass spectrometry, AlphaFold modeling to decipher derive structural model CD95L/BV6-induced necrosome. We identify RIPK1 as central component necrosome, forming core this complex. In addition, provides insights into mechanisms underlying oligomerization, highlighting critical type-II interactions between Death Domains (DDs) FADD assembly RIPK1-mediated complexes. DD necroptosis induction further validated through structure-guided site-directed mutagenesis. Our findings could be useful for pharmacological targeting network treat diseases associated dysregulated inflammation.

Язык: Английский

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Celastrol loaded nanocomplex for painless tumor therapy via YAP inhibition

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Апрель 16, 2025

Язык: Английский

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