Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China.
National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100010, China.
Int J Mol Sci. 2022 Oct 8;23(19):11943. doi: 10.3390/ijms231911943.
Immune evasion and metabolic reprogramming are two fundamental hallmarks of cancer. Interestingly, lactate closely links them together. However, lactate has long been recognized as a metabolic waste product. Lactate and the acidification of the tumor microenvironment (TME) promote key carcinogenesis processes, including angiogenesis, invasion, metastasis, and immune escape. Notably, histone lysine lactylation (Kla) was identified as a novel post-modification (PTM), providing a new perspective on the mechanism by which lactate functions and providing a promising and potential therapy for tumors target. Further studies have confirmed that protein lactylation is essential for lactate to function; it involves important life activities such as glycolysis-related cell functions and macrophage polarization. This review systematically elucidates the role of lactate as an immunosuppressive molecule from the aspects of lactate metabolism and the effects of histone lysine or non-histone lactylation on immune cells; it provides new ideas for further understanding protein lactylation in elucidating lactate regulation of cell metabolism and immune function. We explored the possibility of targeting potential targets in lactate metabolism for cancer treatment. Finally, it is promising to propose a combined strategy inhibiting the glycolytic pathway and immunotherapy.
免疫逃避和代谢重编程是癌症的两个基本特征。有趣的是，乳酸将它们紧密地联系在一起。然而，乳酸长期以来一直被认为是一种代谢废物。乳酸和肿瘤微环境（TME）的酸化促进了关键的致癌过程，包括血管生成、侵袭、转移和免疫逃避。值得注意的是，组蛋白赖氨酸乳酸化（Kla）被鉴定为一种新型的翻译后修饰（PTM），为乳酸发挥作用的机制提供了新的视角，并为肿瘤靶向治疗提供了有希望的潜在治疗方法。进一步的研究证实，蛋白质乳酸化对于乳酸发挥作用至关重要；它涉及糖酵解相关细胞功能和巨噬细胞极化等重要的生命活动。本综述从乳酸代谢和组蛋白赖氨酸或非组蛋白乳酸化对免疫细胞的影响两个方面系统地阐述了乳酸作为免疫抑制分子的作用；它为进一步理解蛋白质乳酸化在阐明乳酸调节细胞代谢和免疫功能方面提供了新的思路。我们探讨了针对乳酸代谢中潜在靶点进行癌症治疗的可能性。最后，提出抑制糖酵解途径和免疫治疗相结合的策略是有希望的。
