Tumor-Intrinsic Cgas-Sting Pathway Activation Contributes to Fasting-Sensitized Immunotherapy in Colorectal Cancer

Published: Jan. 1, 2025

Language: Английский

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Neutrophil extracellular traps impede cancer metastatic seeding via protease-activated receptor 2-mediated downregulation of phagocytic checkpoint CD24

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(2), P. e010813 - e010813

Published: Feb. 1, 2025

Background Phagocytic clearance by macrophages represents a critical immune surveillance mechanism in cancer liver metastasis. Neutrophils, the most abundant cells encountered circulation, play key roles metastasis through neutrophil extracellular traps (NETs). Although NETs promote macrophage phagocytosis during infection, whether they regulate is unknown. The present study aimed to explore of regulating seeding process and mechanisms underlying roles. Methods A lipopolysaccharide-induced NET model was applied role on colorectal (CRC) neutrophils isolated from human peripheral blood were stimulated with PMA release NETs, which collected added cultures different CRC cell lines for vitro studies. Macrophage assessed flow cytometry vivo. RNA-seq microRNA array analyses performed identify pathways regulated downstream molecules. phenotypes evaluated using immunohistochemistry, cytometry, cytokine chemokine arrays. Results both Neutrophil elastase (NE), able inactivate canonical signal protease-activated receptor 2 (PAR2), downregulated phagocytotic checkpoint CD24. Notably, PAR2 deficiency imitated effect Mechanistic studies indicated that inhibiting expression upregulated miR-34a miR-146a CD24 cells. In addition, depletion enhanced recruitment M1 polarization upregulating CSF-1 CXCL1. correlation NETs/NE corroborated specimens. Furthermore, blockade combined an anti-EGFR antibody (cetuximab (CTX)) synergistically phagocytic ability suppressed Conclusions NET-derived inactivated signaling promoted downregulating CD24, functions as Thus, inhibitors CTX may serve novel therapeutic strategy against advanced CRC.

Language: Английский

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CD47 as a potential predictive biomarker in colorectal cancer

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(2), P. e011142 - e011142

Published: Feb. 1, 2025

In this week’s Journal for ImmunoTherapy Cancer, Arai and colleagues analyzed next-generation sequencing data DNA RNA from 14,287 patients with colorectal cancer (CRC) categorized by median CD47 expression level, showed that CD47, a key component of innate immunity in deflecting phagocytosis, is associated molecular subtypes CRC, cell damage-associated pattern-related genes, major oncogenic pathways, adaptive immune checkpoint genes. Taken together, they concluded activation pathways an immune-engaged tumor microenvironment. Clinical outcomes also demonstrated high prolonged survival treated antiangiogenic inhibitor therapy. Biomarker studies such as will enable broader application immuno-oncology to CRC other malignancies.

Language: Английский

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Gut microbiota in colorectal cancer: a review of its influence on tumor immune surveillance and therapeutic response

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: March 5, 2025

Colorectal cancer (CRC) poses a significant global health burden, with gut microbiota emerging as crucial modulator of CRC pathogenesis and therapeutic outcomes. This review synthesizes current evidence on the influence tumor immune surveillance responses to immunotherapies chemotherapy in CRC. We highlight role specific microbial taxa promoting or inhibiting growth potential microbiota-based biomarkers for predicting treatment efficacy. The also discusses implications modulation strategies, including diet, probiotics, fecal transplantation, personalized management. By critically evaluating literature, we aim provide comprehensive understanding microbiota’s dual inform future research directions this field.

Language: Английский

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Combination therapy with immune checkpoint inhibitors in colorectal cancer: Challenges, resistance mechanisms, and the role of microbiota

Biomedicine & Pharmacotherapy, Journal Year: 2025, Volume and Issue: 186, P. 118014 - 118014

Published: March 31, 2025

Language: Английский

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Novel insights into immune-gut microbiota interactions in colorectal cancer: a Mendelian randomization study

Infectious Agents and Cancer, Journal Year: 2025, Volume and Issue: 20(1)

Published: April 18, 2025

The relationship between immune cells and colorectal cancer (CRC) development has been extensively studied; however, the mediating role of gut microbiota in this remains poorly understood. We utilized summary data from genome-wide association studies (GWAS) to analyze 731 cell phenotypes, 473 microbiota, CRC-related data. A two-step mediation analysis was employed identify microbiota. primary method inverse variance weighting (IVW), supplemented by MR-Egger, simple mode, weighted median, mode analyses. Robustness results ensured through systematic sensitivity Our identified 13 phenotypes significantly associated with CRC, including 10 protective factors 3 risk factors. Additionally, showed significant associations comprising 8 5 Mediation revealed that 4-gut (1 order, 1 family, genus, unclassified) mediated CRC. For instance, unclassified CAG - 977 effects FSC-A on NK NKT %lymphocyte CRC risk, proportions 11% 12.3%, respectively. Notably, 22.3% effect EM CD8br %CD8br order Francisellales. This study provides evidence for a potential causal cells, highlighting specific These findings offer new insights into pathogenesis may inform future therapeutic strategies.

Language: Английский

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Genetically Engineered T Cell Membrane-Camouflaged Nanoparticles Triggered Cuproptosis for Synergistic Bladder Cancer Photothermal-Immunotherapy

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 29, 2025

Immunotherapy has become a promising and transformative approach for treating advanced or treatment-resistant bladder cancer (BCa). However, its efficacy remains limited due to the immunosuppressive tumor microenvironment (TME) insufficient immune cell infiltration. Photothermal therapy (PTT), which could cause immunogenic death (ICD) in tissue, been explored as synergistic immunotherapy. Yet, thermal resistance cells often undermines effectiveness of PTT. To address these challenges, we proposed novel strategy that combines PTT with cuproptosis, recently identified form ICD, by engineering Tim-3-overexpressing T membrane-coated nanoparticles (Tim3@PHSM@IC) enhance BCa The overexpression Tim-3 on membrane enabled precise targeting competitively inhibited receptor through recognition Galectin-9. In vitro, Tim3@PHSM@IC effectively induced photothermal cytotoxicity robust cuproptosis. vivo, significantly growth multiple mouse models. Flow cytometry (FCM) RNA sequencing (RNA-seq) analyses revealed reprogrammed TME activating immune-related genes enhancing ICD This study highlights potential overcoming improving immunotherapy integrating

Language: Английский

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Plasma proteome and metabolites profiling reveals dynamics for adverse events and responses after neoadjuvant radiochemotherapy plus PDL1 blockade in microsatellite-stable locally advanced rectal cancer: A prospective longitudinal study

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

Neoadjuvant radio-chemotherapy (nCRT) plus immune checkpoint inhibitors (ICIs) have emerged as an effective antitumor regimen for locally advanced rectal cancer. Yet, few biomarkers are developed to monitor the therapy response. Herein, we investigate longitudinal plasma proteome and metabolites profiling including 117 samples from 50 patients who received nCRT PDL1 blockade therapy. Notably, cholesterol metabolism is activated in disease non-response group during Correspondingly, 1,4-cholestadienone, 7-methyloctanoylcarnitine 3-hydroxybutyrylcarnitine, ABCA13, RAB3IP, GBA2 show significantly positive association with metabolism. Furthermore, by integrating approach, identify a candidate metabolite (phosphatidylcholine, cholest-5-en-23-yn-3beta-ol) (APBB1IP, OLFM4, DNAJC19) that can reflect Above, establish machine learning model predict response, performance validated repeated group-to-group validation accuracy 0.954. Thus, strategy evaluate alteration of identifies panel biomarkers.

Language: Английский

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Recent advances in the development and application of colorectal cancer mouse models

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: May 8, 2025

Colorectal cancer (CRC) remains a significant global health challenge, necessitating the development of reliable preclinical models to advance mechanistic understanding and therapeutic innovation. This review comprehensively examines diverse spectrum rodent employed in CRC research, focusing on their unique characteristics, applications, translational relevance. We systematically evaluate conventional models, including carcinogen-induced genetically engineered mouse (GEMMs), which have been instrumental elucidating tumorigenic pathways genetic drivers. Furthermore, we highlight emergence patient-derived xenografts (PDX) as transformative tool for recapitulating tumor heterogeneity predicting clinical responses. The also explores metastatic are critical studying advanced disease, spontaneous that mimic natural progression. Additionally, discuss growing utility composite animal integrate multiple methodologies better reflect complexity human CRC. By comparing strengths limitations each model system, this provides framework selecting appropriate based specific research objectives. Collectively, these platforms significantly our biology continue drive targeted therapies personalized treatment strategies.

Language: Английский

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Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Cancer Research Communications, Journal Year: 2024, Volume and Issue: 4(2), P. 588 - 606

Published: Feb. 15, 2024

Abstract Neutrophils are a highly heterogeneous cellular population. However, thorough examination of the different transcriptional neutrophil states between health and malignancy has not been performed. We utilized single-cell RNA sequencing human murine datasets, both publicly available independently generated, to identify transcriptomic subtypes developmental lineages in malignancy. Datasets lung, breast, colorectal cancer were integrated establish validate gene signatures. Pseudotime analysis was used genes driving development from cancer. Finally, ligand–receptor interactions signaling pathways neutrophils other immune cell populations primary metastatic investigated. define two main tumors: an activated subtype sharing signatures healthy neutrophils; tumor-specific subtype. This signature is conserved cancer, across tumor types. In metastases, more heterogeneous, exhibiting additional subtypes. implicates IL1β/CXCL8/CXCR2 axis progression metastasis, with effects on T-cell effector function. Functional neutrophil-tumoroid cocultures proliferation assays using orthotopic mouse models lacking Cxcr2 support our analysis. propose that emergence metastatic-specific driven by axis, evolution signals impair function at site. Thus, better understanding programming could optimize immunotherapeutic interventions into early late interventions, targeting states. Significance: recurring demonstrate their staged through allowing for neutrophil-targeting approaches counteract immunosuppressive emerge metastasis.

Language: Английский

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