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.

乳酸 (LA) 通过单羧酸转运蛋白转运系统从肿瘤细胞稳定地流到细胞外空间，抑制抗肿瘤 T 细胞免疫。然而，LA 是一种天然能量代谢物，可以在线粒体中被氧化，并可能刺激 T 细胞。在这里，我们证明降乳酸情绪稳定剂碳酸锂 (LC) 可以抑制 LA 介导的 CD8 ⁺ T 细胞免疫抑制。细胞质 LA 增加了质子泵入溶酶体的速度。LC 干扰液泡 ATP 酶以阻断溶酶体酸化并拯救溶酶体二酰基甘油 - PKCθ 信号，以促进单羧酸转运蛋白 1 定位到线粒体膜，从而将 LA 转运到线粒体作为 CD8 ⁺ T 细胞的能量来源。这些发现表明，使用 LC 靶向 LA 代谢可以支持癌症免疫治疗。