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<p>While premetastatic niche formation is known to affect primary tumors lung metastases, the role of lung stromal cells in this process remains unclear. Here, by performing multiomics sequencing, we identify interferon-regulated CD34<sup>+</sup>fibroblasts that reshape the immunosuppressive lung microenvironment via VLDLR-mediated lipoprotein metabolism activation. Increased lipoprotein uptake facilitates intracellular lipid accumulation, followed by CD155 expression in fibroblasts. CD155<sup>+</sup>fibroblasts strongly induce cytotoxic CD8<sup>+</sup>T and NK cell exhaustion, resulting in the formation of a premetastatic niche. The genetic disruption of the interferon–VLDLR–CD155 axis robustly reinstates immune surveillance and suppresses lung metastasis in multiple tumor models. Notably, interferon-based therapy is potentiated by specific silencing of the interferon response in fibroblasts or CD155 blockade. Moreover, the FTO-YTHDF2-mediated STAT1 m<sup>6</sup>A modification results in differences in the interferon response. Collectively, our findings reveal how interferon-induced metabolic rewiring in fibroblasts promotes metastatic competence via CD155-mediated immune evasion, suggesting stromal-targeted strategies for treating lung metastasis.</p>

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Interferon-elicited lipoprotein metabolism in lung fibroblasts facilitates premetastatic niche formation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • Jian Gao,
  • Yilan Huang,
  • Xiaojun Zhang,
  • Chao Gao,
  • Yiran Zhuang,
  • Zheng Han,
  • Mingyu Xia,
  • Chun Jin,
  • Dingguo Wang,
  • Lingxian Zhang,
  • Jiazhe Wen,
  • Lefan Jin,
  • Yongqiang Ao,
  • Jiahao Jiang,
  • Jianyong Ding

摘要

While premetastatic niche formation is known to affect primary tumors lung metastases, the role of lung stromal cells in this process remains unclear. Here, by performing multiomics sequencing, we identify interferon-regulated CD34+fibroblasts that reshape the immunosuppressive lung microenvironment via VLDLR-mediated lipoprotein metabolism activation. Increased lipoprotein uptake facilitates intracellular lipid accumulation, followed by CD155 expression in fibroblasts. CD155+fibroblasts strongly induce cytotoxic CD8+T and NK cell exhaustion, resulting in the formation of a premetastatic niche. The genetic disruption of the interferon–VLDLR–CD155 axis robustly reinstates immune surveillance and suppresses lung metastasis in multiple tumor models. Notably, interferon-based therapy is potentiated by specific silencing of the interferon response in fibroblasts or CD155 blockade. Moreover, the FTO-YTHDF2-mediated STAT1 m6A modification results in differences in the interferon response. Collectively, our findings reveal how interferon-induced metabolic rewiring in fibroblasts promotes metastatic competence via CD155-mediated immune evasion, suggesting stromal-targeted strategies for treating lung metastasis.