Towards therapeutic exploitation of tumor addiction to fatty acids under acidosis

Cancer progression is influenced by the physico-chemical features of the tumor microenvironment. Considered as a major hallmark of cancer, tumor acidosis results from an exacerbated glycolytic metabolism and an insufficient clearance of protons by the vasculature. Hence, tumors have been described as more acidic than healthy tissues. Cancer cells will shift their metabolic preferences from glucose towards fatty acids (FAs) to adapt to this hostile environment and thereby will gain further advantages to survive, proliferate and metastasize. We examined whether promoting an excess uptake of specific FAs could lead to antitumor effects in these acidosis-adapted cancer cells. We found that n-3 but also n-6 polyunsaturated FAs (PUFAs) selectively induced ferroptosis in cancer cells under ambient acidosis. Upon exceeding the buffering capacity of lipid droplets, n-3 and n-6 PUFA peroxidation accounted for cytotoxic effects and even more so if their storage or beta-oxidation was inhibited. Finally, an n-3 PUFA-rich diet significantly delayed mouse tumor growth when compared to a control diet. The therapeutic potential of PUFA supplementation was further evaluated by studying the administration of n-3 PUFA-rich capsules to human volunteers. Altogether, our data point out dietary PUFAs as a selective adjuvant antitumor modality that may efficiently complement pharmacological approaches.