Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria
Jingwei Ma, Liang Tang, Yaoyao Tan, Jingxuan Xiao, Keke Wei, Xin Zhang, Yuan Ma, Shuai Tong, Jie Chen, Nannan Zhou, Li Yang, Lei Zhang, Yonggang Li, Jiadi Lv, Junwei Liu, Huafeng Zhang, Ke Tang, Yi Zhang, Bo Huang
Abstract
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 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.