Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria

Abstract The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8 + T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol–PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus…

• NN
  National Natural Science Foundation of China

  Awards: 91942314, 32090053, 82388201
• ZU
  Zhengzhou University
• WU
  Wuhan Union Hospital
• TM
  Tongji Medical College, Huazhong University of Science and Technology