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Targeting the lactic acid metabolic pathway for antitumor therapy - PubMed

  • ️Sun Jan 01 2023

Review

Targeting the lactic acid metabolic pathway for antitumor therapy

Zhi Li et al. Mol Ther Oncolytics. 2023.

Abstract

Lactic acid is one of the most abundant products of cellular metabolism and has historically been considered a cell-damaging metabolic product. However, as research has deepened, the beneficial effects of lactic acid on tumor cells and the tumor microenvironment have received increasing attention from the oncology community. Lactic acid can not only provide tumor cells with energy but also act as a messenger molecule that promotes tumor growth and progression and protects tumor cells from immune cells and killing by radiation and chemotherapy. Thus, the inhibition of tumor cell lactic acid metabolism has emerged as a novel antitumor treatment strategy that can also effectively enhance the efficacy of conventional antitumor therapies. In this review, we classify the currently available therapies targeting lactic acid metabolism and examine their prospects for clinical application.

Keywords: acidic tumor microenvironment; cancer; drug delivery; lactic acid metabolism; targeted therapy.

© 2023 The Author(s).

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Conflict of interest statement

Both of the authors report no conflicts of interest.

Figures

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Graphical abstract
Figure 1
Figure 1

Lactic acid plays a dual role in the TME Lactic acid serves as both the end product of tumor cell metabolism (in anaerobic tumors) and the energy source for tumor cells (in aerobic tumors). Moreover, it can have both inhibitory and activating effects on immune cell function. Overall, the activating effect of lactic acid on tumors is prominent, because it not only promotes tumor energy production but also facilitates immune the evasion of immune system surveillance by tumor cells. ATP, adenosine triphosphate; DCs, dendritic cells; F-6-P, fructose-6-phosphate; G-6-P, glucose-6-phosphate; GLUT4, glucose transporter 4; LDH, lactate dehydrogenase; MCT1, monocarboxylate transporter 1; MCT4, monocarboxylate transporter 4; MDSC, myeloid-derived suppressor cell; NAD+, nicotinamide-adenine dinucleotide; NADH, reduced form of nicotinamide-adenine dinucleotide; NK cells, natural killer cells; TCA, tricarboxylic acid cycle; Treg, regulatory T lymphocytes.

Figure 2
Figure 2

Lactic acid plays an important role as a signaling molecule in tumor cells Lactic acid may trigger downstream signaling pathways via MCT1 or GPR81, resulting in several tumor-promoting effects, such as tumor cell growth and proliferation, epithelial-mesenchymal transformation, angiogenesis, and immune evasion and chemotherapy resistance. AREG, EGFR ligand amphiregulin, XX; bFGF, basic fibroblast growth factor;EMT, epithelial-mesenchymal transition; GPR81, G protein-coupled receptor 81; HGF, hepatocyte growth factor; MCT1, monocarboxylate transporter; MET, mesenchymal epithelial transitionfactor; STAT3, signal transducer and activator of transcription 3; TAZ, XX; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor.

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