Mortazavi Farsani Seyedeh Sahar, Verma Vivek
Section of Cancer Immunotherapy and Immune Metabolism, The Hormel Institute, University of Minnesota, Austin, MN, United States.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States.
Front Oncol. 2023 May 10;13:1175532. doi: 10.3389/fonc.2023.1175532. eCollection 2023.
Metabolism is central to energy generation and cell signaling in all life forms. Cancer cells rely heavily on glucose metabolism wherein glucose is primarily converted to lactate even in adequate oxygen conditions, a process famously known as "the Warburg effect." In addition to cancer cells, Warburg effect was found to be operational in other cell types, including actively proliferating immune cells. According to current dogma, pyruvate is the end product of glycolysis that is converted into lactate in normal cells, particularly under hypoxic conditions. However, several recent observations suggest that the final product of glycolysis may be lactate, which is produced irrespective of oxygen concentrations. Traditionally, glucose-derived lactate can have three fates: it can be used as a fuel in the TCA cycle or lipid synthesis; it can be converted back into pyruvate in the cytosol that feeds into the mitochondrial TCA; or, at very high concentrations, accumulated lactate in the cytosol may be released from cells that act as an oncometabolite. In immune cells as well, glucose-derived lactate seems to play a major role in metabolism and cell signaling. However, immune cells are much more sensitive to lactate concentrations, as higher lactate levels have been found to inhibit immune cell function. Thus, tumor cell-derived lactate may serve as a major player in deciding the response and resistance to immune cell-directed therapies. In the current review, we will provide a comprehensive overview of the glycolytic process in eukaryotic cells with a special focus on the fate of pyruvate and lactate in tumor and immune cells. We will also review the evidence supporting the idea that lactate, not pyruvate, is the end product of glycolysis. In addition, we will discuss the impact of glucose-lactate-mediated cross-talk between tumor and immune cells on the therapeutic outcomes after immunotherapy.
代谢是所有生命形式中能量产生和细胞信号传导的核心。癌细胞严重依赖葡萄糖代谢，即使在充足的氧气条件下，葡萄糖也主要转化为乳酸，这一过程就是著名的“瓦伯格效应”。除癌细胞外，还发现瓦伯格效应在其他细胞类型中也存在，包括活跃增殖的免疫细胞。根据目前的理论，丙酮酸是糖酵解的终产物，在正常细胞中，尤其是在缺氧条件下，丙酮酸会转化为乳酸。然而，最近的一些观察结果表明，糖酵解的最终产物可能是乳酸，其产生与氧气浓度无关。传统上，葡萄糖衍生的乳酸有三种去向：它可以作为三羧酸循环或脂质合成的燃料；它可以在细胞质中转化回丙酮酸，然后进入线粒体三羧酸循环；或者，在非常高的浓度下，细胞质中积累的乳酸可能会从细胞中释放出来，作为一种肿瘤代谢物。在免疫细胞中，葡萄糖衍生的乳酸似乎在代谢和细胞信号传导中也起着重要作用。然而，免疫细胞对乳酸浓度更为敏感，因为已发现较高的乳酸水平会抑制免疫细胞功能。因此，肿瘤细胞衍生的乳酸可能是决定对免疫细胞导向疗法反应和抗性的主要因素。在本综述中，我们将全面概述真核细胞中的糖酵解过程，特别关注丙酮酸和乳酸在肿瘤细胞和免疫细胞中的去向。我们还将回顾支持乳酸而非丙酮酸是糖酵解终产物这一观点的证据。此外，我们将讨论肿瘤细胞和免疫细胞之间葡萄糖 - 乳酸介导的相互作用对免疫治疗后治疗结果的影响。
