Lactate-Lactylation Hands between Metabolic Reprogramming and Immunosuppression

Abstract

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.

Lactate regulators contribute to tumor microenvironment and predict prognosis in lung adenocarcinoma

“…DNA methylation of lactate regulators has a significant negative correlation with the expression of genes, which demonstrates that DNA methylation regulates expression of those genes that were associated with abnormal metabolism of the tumor. The acidification of the tumor microenvironment is an important cause of carcinogenesis processes, including metastasis and immune escape (28). The increase in lactate in the tumor is more consistent with tumor growth and migration.…”

Dual Roles of Lactate in EGFR-TKI-Resistant Lung Cancer by Targeting GPR81 and MCT1

“…Histone lactylation is frst reported to promote homeostasis of macrophages during infection, and more and more studies have focused its role in cancer. Not only dose histone lactylation regulate oncogenes in the process of tumorigenesis of cancer cells, but facilitates immunosuppression of tumor-infltrating myeloid cells and regulatory T cells [26][27][28]. A recent work by Jiang et al showed that lactate induces transcriptional activation of HIF1a in lung cancer, which in turn activates transcription of genes that facilitate glucose uptake and glycolysis resulting in lactate generation with a sort of positive feedback [29].…”

Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment

“…Macrophages are the most numerous white blood cells in TME, and TAMs play a key regulatory role in the occurrence and development of tumors. Exosomal ncR-NAs secreted by TAMs can affect the metabolic state of tumor cells [284]. In recent studies, macrophages-derived exosomal miR-503-3p targets DACT2, activates the Wnt/β-catenin signaling pathway, promotes glycolysis and reduces mitochondrial OXPHOS in BC cells [263].…”