Tumor acidosis supports cancer cell lipid uptake via a rapid transporter-independent mechanism.

Tumor acidosis alters cancer cell metabolism and favors aggressive disease progression. Cancer cells in acidic environments increase lipid droplet accumulation and oxidative phosphorylation, which are characteristics of aggressive cancers. Here, we used live imaging, shotgun lipidomics and immunofluorescence analyses of mammary and pancreatic cancer cells to demonstrate that both acute acidosis and adaptation to acidic growth drive rapid uptake of fatty acids (FAs), which are converted to triacylglycerols and stored in lipid droplets. Consistent with being independent of de novo synthesis, triacylglycerol and lipid droplet accumulation in acid-adapted cells was unaffected by FA synthetase (FAS, encoded by FASN) inhibitors. Macropinocytosis, which is upregulated in acid-adapted cells, partially contributed to FA uptake, which was independent of other protein-facilitated lipid uptake mechanisms, including uptake via CD36 and FATP2, and caveolin- and clathrin-dependent endocytosis. We propose that a major mechanism by which tumor acidosis drives FA uptake is through neutralizing protonation of negatively charged FAs allowing their diffusive, transporter-independent uptake. We suggest that this could be a major factor triggering acidosis-driven metabolic rewiring.