恶性浆细胞（PCs）的代谢变化和对肿瘤微环境的适应是多发性骨髓瘤（MM）的标志之一。我们以前已经表明，MM间充质基质细胞比健康对照组更具有糖酵解能力并产生更多乳酸。因此，我们旨在探讨高乳酸浓度对肿瘤PCs代谢及其对蛋白酶体抑制剂（PIs）疗效的影响。通过比色法在MM患者血清中测定乳酸浓度。乳酸处理的MM细胞的代谢通过海马和实时聚合酶链反应（PCR）进行评估。细胞流式仪用于评估线粒体反应性氧物种（mROS）、凋亡和线粒体去极化。MM患者血清中乳酸浓度升高。因此，我们用乳酸处理PCs，并观察到氧化磷酸化相关基因、mROS和氧气消耗速率的增加。乳酸补充剂显著降低了细胞增殖并且对PIs反应不敏感。这些数据通过药理学抑制单羧酸转运体1（MCT1）的AZD3965得到了确认，它能够克服乳酸对PIs的代谢保护效应。一致地，高水平的循环乳酸导致Treg和单核型骨髓来源性抑制细胞的扩张，而AZD3965显著减少了这种效应。总体来说，这些发现表明，靶向TME中的乳酸转运抑制了肿瘤PCs的代谢重构、乳酸依赖性免疫逃逸，从而提高了治疗效果。 ©2023作者们。由北京干细胞与再生医学研究所和约翰威利公司出版的《细胞增殖》杂志。

Metabolic changes of malignant plasma cells (PCs) and adaptation to tumour microenvironment represent one of the hallmarks of multiple myeloma (MM). We previously showed that MM mesenchymal stromal cells are more glycolytic and produce more lactate than healthy counterpart. Hence, we aimed to explore the impact of high lactate concentration on metabolism of tumour PCs and its impact on the efficacy of proteasome inhibitors (PIs). Lactate concentration was performed by colorimetric assay on MM patient's sera. The metabolism of MM cell treated with lactate was assessed by seahorse and real time Polymerase Chain Reaction (PCR). Cytometry was used to evaluate mitochondrial reactive oxygen species (mROS), apoptosis and mitochondrial depolarization. Lactate concentration resulted increased in MM patient's sera. Therefore, PCs were treated with lactate and we observed an increase of oxidative phosphorylation-related genes, mROS and oxygen consumption rate. Lactate supplementation exhibited a significant reduction in cell proliferation and less responsive to PIs. These data were confirmed by pharmacological inhibition of monocarboxylate transporter 1 (MCT1) by AZD3965 which was able to overcame metabolic protective effect of lactate against PIs. Consistently, high levels of circulating lactate caused expansion of Treg and monocytic myeloid derived suppressor cells and such effect was significantly reduced by AZD3965. Overall, these findings showed that targeting lactate trafficking in TME inhibits metabolic rewiring of tumour PCs, lactate-dependent immune evasion and thus improving therapy efficacy.© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.