Cell-derived lactate triggers local hydrogelation and phenotype remodelling

Abstract

Abstract Many tumours release lactate as a major metabolic product and signalling molecule. Here we use lactate flux as an endogenous trigger for covalent hydrogel formation. Phenol-functionalised alginate remains soluble until cell-derived lactate is oxidised by lactate oxidase; the generated hydrogen peroxide is used by horseradish peroxidase to crosslink phenols and form a matrix at metabolically active sites. Hydrogels form within minutes and reach storage moduli from approximately 10 Pa to 5 kPa. In tumour-spheroid models, including a patient-derived glioblastoma spheroid model, local lactate production generates spatially confined gelation that extended up to around 1 mm from the spheroid surface. Nanoindentation and fluorescence correlation spectroscopy reveal radial stiffness and polymer-density gradients, while proteome profiling and imaging indicate reduced proliferative signalling and increased markers associated with migration and matrix remodelling. These findings establish metabolite-gated hydrogelation as a strategy to couple cellular metabolism to covalent matrix assembly, mechanics and transport, providing a bio-synthetic platform for modelling cell–matrix reciprocity and tumour confinement.