Jiang Mengqian, Wang Yuanchun, Zhao Xiaoyong, Yu Jinming
School of Clinical Medicine, Shandong Second Medical University, Weifang, China.
Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Front Immunol. 2024 Nov 25;15:1492050. doi: 10.3389/fimmu.2024.1492050. eCollection 2024.
Lactic acid, a key metabolic byproduct within the tumor microenvironment, has garnered significant attention for its role in immune evasion mechanisms. Tumor cells produce and release large amounts of lactic acid into the tumor microenvironment through aberrant glycolysis via the Warburg effect, leading to a drop in pH. Elevated lactic acid levels profoundly suppress proliferation capacity, cytotoxic functions, and migratory abilities of immune effector cells such as macrophages and natural killer cells at the tumor site. Moreover, lactic acid can modulate the expression of surface molecules on immune cells, interfering with their recognition and attack of tumor cells, and it regulates signaling pathways that promote the expansion and enhanced function of immunosuppressive cells like regulatory T cells, thereby fostering immune tolerance within the tumor microenvironment. Current research is actively exploring strategies targeting lactic acid metabolism to ameliorate tumor immune evasion. Key approaches under investigation include inhibiting the activity of critical enzymes in lactic acid production to reduce its synthesis or blocking lactate transporters to alter intracellular and extracellular lactate distribution. These methods hold promise when combined with existing immunotherapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies to enhance the immune system's ability to eliminate tumor cells. This could pave the way for novel combinatorial treatment strategies in clinical cancer therapy, effectively overcoming tumor immune evasion phenomena, and ultimately improving overall treatment efficacy.
乳酸是肿瘤微环境中的一种关键代谢副产物，因其在免疫逃逸机制中的作用而备受关注。肿瘤细胞通过瓦伯格效应经由异常糖酵解在肿瘤微环境中产生并释放大量乳酸，导致pH值下降。肿瘤部位升高的乳酸水平会显著抑制免疫效应细胞（如巨噬细胞和自然杀伤细胞）的增殖能力、细胞毒性功能及迁移能力。此外，乳酸可调节免疫细胞表面分子的表达，干扰其对肿瘤细胞的识别与攻击，并调控促进调节性T细胞等免疫抑制细胞扩增及功能增强的信号通路，从而在肿瘤微环境中促进免疫耐受。当前研究正在积极探索针对乳酸代谢的策略以改善肿瘤免疫逃逸。正在研究的关键方法包括抑制乳酸生成中关键酶的活性以减少其合成，或阻断乳酸转运体以改变细胞内和细胞外的乳酸分布。这些方法与现有的免疫疗法（如免疫检查点抑制剂和嵌合抗原受体T细胞疗法）联合使用时有望增强免疫系统清除肿瘤细胞的能力。这可能为临床癌症治疗中的新型联合治疗策略铺平道路，有效克服肿瘤免疫逃逸现象，并最终提高整体治疗效果。
