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<p>Glucose deficiency promotes the secretion of cytokines and inflammatory factors to rewire the immune compartment and restore blood flow. Here we show that cancer cells subjected to glucose deprivation or hypoxia, but not to other metabolic stressors, secrete LIF, an interleukin-6 family cytokine implicated in the development of solid tumours. We find that mannose supplementation prevents LIF release by sustaining multiple metabolic pathways in the absence of glucose. Mechanistically, LIF release is associated with impairment of <i>N</i>-glycosylation and activation of PERK and MEK MAP kinases. In mouse models of non-small-cell lung cancer, reduction of LIF impairs angiogenesis and tumour growth, rewires the immune system toward an antitumour phenotype and inhibits tumour implantation in the lung. In individuals with non-small-cell lung cancer, LIF levels correlate with markers of hypoxia, glucose deprivation and angiogenesis. Overall, these findings identify LIF as a metabolic stress-induced cytokine that could be targeted to disrupt adaptive responses in cancer.</p>

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Glucose deprivation drives LIF-dependent lung cancer

  • 期刊论文

  • 发表日期：

    2026年1月30日

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  • Fedra Luciano-Mateo,
  • Joaquim Moreno-Caceres,
  • Miguel Hernández-Madrigal,
  • Franziska Püschel,
  • Lidia Collado-Rodriguez,
  • Francesca Favaro,
  • Sara Hijazo-Pechero,
  • Mabel Cruz-Rodríguez,
  • Felipe Jiménez-Hernández,
  • Verónica Villagrasa-Araya,
  • Nil Figueras-Duch,
  • Jaime Redondo-Pedraza,
  • Didac Palau-Gallinat,
  • Silvia Plans-Marin,
  • Agnés Figueras,
  • Pedro Fuentes Varela,
  • Lidia de Benito-Gómez,
  • Antonio Gentilella,
  • José Carlos Perales,
  • Xavier Solé,
  • Andrés Méndez-Lucas,
  • Francesc Viñals,
  • Ernest Nadal,
  • Cristina Muñoz-Pinedo

摘要

Glucose deficiency promotes the secretion of cytokines and inflammatory factors to rewire the immune compartment and restore blood flow. Here we show that cancer cells subjected to glucose deprivation or hypoxia, but not to other metabolic stressors, secrete LIF, an interleukin-6 family cytokine implicated in the development of solid tumours. We find that mannose supplementation prevents LIF release by sustaining multiple metabolic pathways in the absence of glucose. Mechanistically, LIF release is associated with impairment of N-glycosylation and activation of PERK and MEK MAP kinases. In mouse models of non-small-cell lung cancer, reduction of LIF impairs angiogenesis and tumour growth, rewires the immune system toward an antitumour phenotype and inhibits tumour implantation in the lung. In individuals with non-small-cell lung cancer, LIF levels correlate with markers of hypoxia, glucose deprivation and angiogenesis. Overall, these findings identify LIF as a metabolic stress-induced cytokine that could be targeted to disrupt adaptive responses in cancer.