Lactate and lactylation in cancer

Area of Science:

• Biochemistry
• Cancer Biology
• Immunology

Background:

• Lactate plays a critical role in cellular differentiation and fate regulation in both normal physiology and disease, especially cancer.
• The tumor microenvironment (TME) is significantly shaped by lactate's effects on various cell types, including tumor cells, immune cells, and stromal cells.

Purpose of the Study:

• To review the multifaceted roles of lactate in cancer progression and its impact on the tumor microenvironment.
• To explore therapeutic strategies targeting lactate metabolism for cancer treatment.

Main Methods:

• Literature review focusing on lactate's influence on cellular processes within the TME.
• Analysis of lactate production and transport mechanisms, including lactate dehydrogenase (LDH) and monocarboxylate transporters (MCT).
• Examination of the therapeutic potential of targeting LDH and MCT in combination with immunotherapy.

Main Results:

• Lactate influences tumor cell signaling, oxidative stress resistance, and lactylation.
• Lactate modulates immune cell differentiation, immune response, and surveillance within the TME.
• Lactate affects stromal and endothelial cells, contributing to extracellular matrix remodeling, epithelial-mesenchymal transitions (EMT), angiogenesis, and drug resistance.

Conclusions:

• Targeting lactate metabolism, particularly through LDH and MCT inhibition, presents a "Heel of Achilles" for cancer treatment.
• Inhibitors of LDH and MCT demonstrate potential as tumor suppressors and can synergistically enhance immunotherapy outcomes.