华中科技大学黄波团队发现，碳酸锂通过将乳酸分流到线粒体来使肿瘤反应性CD8⁺ T细胞恢复活力。这一研究成果于2024年1月23日在线发表在国际学术期刊《自然—免疫学》上。

研究人员发现降低乳酸盐的情绪稳定剂碳酸锂（LC）可以抑制乳酸（LA）介导的CD8⁺ T细胞免疫抑制。细胞质中的LA增加了泵送质子到溶酶体的速度。LC干扰空泡ATP酶，从而阻止溶酶体酸化，并挽救溶酶体二酰甘油-PKCθ信号传导，促进单羧酸盐转运体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，利用LC靶向LA代谢可支持癌症免疫疗法。

据介绍，LA通过单羧酸转运体交感系统从肿瘤细胞稳定地流向细胞外空间，从而抑制了抗肿瘤T细胞免疫。然而，LA是一种天然的能量代谢产物，可在线粒体中氧化，并有可能刺激T细胞。

附：英文原文

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

Author: Ma, Jingwei, Tang, Liang, Tan, Yaoyao, Xiao, Jingxuan, Wei, Keke, Zhang, Xin, Ma, Yuan, Tong, Shuai, Chen, Jie, Zhou, Nannan, Yang, Li, Lei, Zhang, Li, Yonggang, Lv, Jiadi, Liu, Junwei, Zhang, Huafeng, Tang, Ke, Zhang, Yi, Huang, Bo

Issue&Volume: 2024-01-23

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.

DOI: 10.1038/s41590-023-01738-0

Source: https://www.nature.com/articles/s41590-023-01738-0