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<p>Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1—replacing heparan sulfate with CS—thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol <i>O</i>-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.</p>

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Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月11日

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  • Anna Bång-Rudenstam,
  • Myriam Cerezo-Magaña,
  • Marton Horvath,
  • Hugo Talbot,
  • Emma Gustafsson,
  • Stevanus Jonathan,
  • Chaitali Chakraborty,
  • Itzel Nissen,
  • Kelin Gonçalves de Oliveira,
  • Axel Boukredine,
  • Sarah Beyer,
  • Julio Enriquez Perez,
  • Maria C. Johansson,
  • Lena Kjellén,
  • Emil Tykesson,
  • Anders Malmström,
  • Toin H. van Kuppevelt,
  • Karin Forsberg-Nilsson,
  • Jeffrey D. Esko,
  • Silvia Remeseiro,
  • Johan Bengzon,
  • Valeria Governa,
  • Mattias Belting

摘要

Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1—replacing heparan sulfate with CS—thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.