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<p>Whether a distinct subset of cancer stem cells (CSCs) is exclusively responsible for metastasis and how this process occurs remain unresolved. Through multi-omics, pan-cancer analysis and multiple tumour-bearing models, we identify THY1⁺ CSCs as the key drivers of metastasis and uncover a previously unrecognized ‘pseudohypoxic’ state (independent of classical hypoxia) as a central regulatory factor. The self-renewal of THY1⁺ CSCs is maintained by IL-6–MYC signalling. Upon encountering neutrophils, THY1⁺ CSCs activate the THY1–Mac1 axis, triggering the Src–Akt/Erk pathway, Rac1 activation and a migrasome-dependent process that induces neutrophils to expel reactive oxygen species-enriched damaged mitochondria. THY1 signalling further enhances macropinocytosis, enabling CSCs to internalize these mitochondria and adopt a pseudohypoxic state, thereby facilitating CSC metastasis. Notably, targeting the IL-6–Myc, THY1–Mac1 or Src–Akt/Erk signalling pathways effectively suppresses pseudohypoxia-driven CSC metastasis. These findings unveil previously unexplored mechanisms by which CSCs undergo metastasis, offering potential strategies to combat tumour metastasis and improve cancer prognosis.</p>

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THY1+ cancer stem cells drive metastasis through a pseudohypoxic state shaped by neutrophil-derived mitochondria

  • 期刊论文

  • 发表日期：

    2026年2月12日

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  • Wen-Hua Wan,
  • Pei-Lin Li,
  • Wen-Jie Cao,
  • Zheng-Xi Li,
  • Yu-Qi Xin,
  • Jun-Cheng Wang,
  • Lei Chen,
  • Lianxin Liu,
  • Muyan Cai,
  • Limin Zheng,
  • Xiang-Ming Lao,
  • Yuan Wei,
  • Dong-Ming Kuang

摘要

Whether a distinct subset of cancer stem cells (CSCs) is exclusively responsible for metastasis and how this process occurs remain unresolved. Through multi-omics, pan-cancer analysis and multiple tumour-bearing models, we identify THY1⁺ CSCs as the key drivers of metastasis and uncover a previously unrecognized ‘pseudohypoxic’ state (independent of classical hypoxia) as a central regulatory factor. The self-renewal of THY1⁺ CSCs is maintained by IL-6–MYC signalling. Upon encountering neutrophils, THY1⁺ CSCs activate the THY1–Mac1 axis, triggering the Src–Akt/Erk pathway, Rac1 activation and a migrasome-dependent process that induces neutrophils to expel reactive oxygen species-enriched damaged mitochondria. THY1 signalling further enhances macropinocytosis, enabling CSCs to internalize these mitochondria and adopt a pseudohypoxic state, thereby facilitating CSC metastasis. Notably, targeting the IL-6–Myc, THY1–Mac1 or Src–Akt/Erk signalling pathways effectively suppresses pseudohypoxia-driven CSC metastasis. These findings unveil previously unexplored mechanisms by which CSCs undergo metastasis, offering potential strategies to combat tumour metastasis and improve cancer prognosis.