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<p>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.</p>

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GPR4 promotes immune exclusion in colon cancer through LOXL2-mediated extracellular matrix remodeling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月24日

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  • Shuheng Bai,
  • Min Chen,
  • Xuan Wang,
  • Ning Lan,
  • Ruijie Meng,
  • Yanli Yan,
  • Wanyi Liu,
  • Wenyang Li,
  • Fang Wu,
  • Xiangxiang Zhang,
  • Fengyuan Hu,
  • Rong Li,
  • Juan Ren

摘要

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.