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

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.