Tumor Acidosis Remodels the Glycocalyx to Control Lipid Scavenging and Ferroptosis

Aggressive tumours are defined by their ability to adapt to microenvironmental stress and reprogram cellular metabolism to promote therapy resistance. 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 through scavenging of extracellular lipids. However, how tumour cells coordinate these processes under metabolic stress remains poorly understood. Here, using integrated analyses of patient tumours, primary patient-derived 3D models, and in vivo systems, we identify a chondroitin sulphate (CS)-enriched glycocalyx as a hallmark of the acidic tumour microenvironment in glioblastoma and CNS metastases. This CS-rich glycocalyx encapsulates tumour cells, limits the uptake of extracellular lipid particles, and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging HIF and TGFβ signalling induces a glycan switch on syndecan-1 - replacing heparan sulphate with CS - thereby impairing its lipid scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol-O-acyltransferase 1, a critical enzyme in LD formation, triggers catastrophic lipid peroxidation and robust 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.