Repression of ferroptotic cell death mediated antitumor immunity by mitochondrial calcium signaling

Ferroptosis is a unique type of programmed cell death caused by excessive lipid peroxidation and represents a vulnerability in certain types of cancer. However, the signaling mechanisms that modulate ferroptosis and its functional consequence on the tumor microenvironment are poorly understood. Here, we demonstrate an inhibitory effect of mitochondrial calcium uniporter (MCU) on ferroptosis during embryogenesis and tumor development. MCU-dependent production of metabolite acetyl-coenzyme A (acetyl-CoA) supports the normal function of glutathione peroxidase 4 (GPX4), a critical gatekeeper of ferroptosis. Mechanistically, acetylation of GPX4 on lysine 90 (K90) prevents the formation of a detrimental salt bridge between K90 and aspartate 23, therefore protecting GPX4 enzymatic activity and avoiding ferroptosis. Deletion of MCU in cancer cells caused a robust antitumor T cell response and significantly blunted tumor growth. Thus, our findings indicate MCU-mediated acetyl-CoA metabolism as a critical anti-ferroptosis mechanism, which can be investigated as potential therapeutic candidate for tumor treatment.