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

Nat Immunol. 2024 Mar;25(3):552-561. doi: 10.1038/s41590-023-01738-0. Epub 2024 Jan 23.


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 transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.

MeSH terms

  • Antimanic Agents* / pharmacology
  • CD8-Positive T-Lymphocytes
  • Humans
  • Lactic Acid* / metabolism
  • Lithium Carbonate* / pharmacology
  • Mitochondria* / drug effects
  • Mitochondria* / metabolism
  • Neoplasms* / metabolism


  • Lactic Acid
  • Lithium Carbonate
  • Antimanic Agents