ArticleNature communications2025
GPR4 promotes immune exclusion in colon cancer through LOXL2-mediated extracellular matrix remodeling.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed.
- Mechano-immunomodulatory biomaterials: From immune mechanosensing to translational design.Bioactive materials · 2026Review
- Spatial ecotype in tumor immune exclusion: from spatial architecture to therapeutic strategies.Molecular cancer · 2026Review
- Review
- Targeting the Barriers Driving Immune Exclusion.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Multidrug resistance in cancer: current understandings and future perspective.Molecular biomedicine · 2026Review
- DDR2-COL11A1 Transcriptional Coupling as a Candidate Therapeutic Target in Colorectal Cancer: Integrative Transcriptomic and Deep Learning Validation.International journal of molecular sciences · 2026Article
- Mechanical properties of the tumor microenvironment: drivers of immunotherapy resistance in solid tumors.Frontiers in immunology · 2026Review
- Traditional Chinese medicine remodels the immune microenvironment of colorectal cancer: mechanisms and therapeutic perspectives.Frontiers in immunology · 2026Review
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
Immune exclusion is associated with adverse prognosis in tumors, and this phenomenon may be facilitated by a physical barrier constituted by the extracellular matrix (ECM). Hypoxia and acidity promote immune exclusion, however the detailed mechanism remains unclear. This study demonstrate that G-protein-coupled-receptor-4 (GPR4), as a proton sensor, induces immune exclusion in colon cancer by promoting collagen fiber alignment and deposition. Specifically, GPR4 facilitates collagen alignment via LOXL2 regulation and enhances collagen I by modulating TGF-β, both mediated by the JAK2/STAT3 pathway. We further validate our findings in a male animal model, observing that elevated GPR4 expression in colon cancer results in an immune-excluded microenvironment. Inhibition of the JAK2/STAT3 pathway and LOXL2 function effectively reverse immune exclusion and enhance immunotherapy efficacy. Collectively, our findings elucidate a mechanism of immune exclusion and propose a potential target for improving the therapeutic efficacy of immunotherapy through the remodeling of the tumor ECM.
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Registered trials
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