Lactate and lactylation in cancer

Abstract

Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings, particularly in intricate conditions such as cancer. Specifically, lactate has been demonstrated to be pivotal in molding the tumor microenvironment (TME) through its effects on different cell populations. Within tumor cells, lactate impacts cell signaling pathways, augments the lactate shuttle process, boosts resistance to oxidative stress, and contributes to lactylation. In various cellular populations, the interplay between lactate and immune cells governs processes such as cell differentiation, immune response, immune surveillance, and treatment effectiveness. Furthermore, communication between lactate and stromal/endothelial cells supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, and drug resistance. Focusing on lactate production and transport, specifically through lactate dehydrogenase (LDH) and monocarboxylate transporters (MCT), has shown promise in the treatment of cancer. Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy, leading to a synergistic therapeutic effect when combined with immunotherapy. The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism, highlighting the Heel of Achilles for cancer treatment.

Fig. 1

Lactate/Lactylation-targeted therapy stands for the Heel of Achilles for cancer treatment. Lactate/lactylation-targeted therapy mitigates the impact of lactate/lactylation on onco-metabolic reprogramming and tumor microenvironment (TME) remodeling, underscoring the Heel of Achilles for cancer treatment. Generated using Adobe Illustrator (Version 28.2). Abbreviations: BM basal membrane, CAFs cancer-associated fibroblasts; EMT epithelial-mesenchymal transitions; LDHA lactate dehydrogenase A

Fig. 2

Milestone events of research on lactate metabolism and lactylation. Since lactate was first discovered in 1780, its metabolic role and significance in tumors have gradually been clarified. With advances in isotope-tracing systems, single-cell sequencing, and probe-based metabolic imaging, the biological properties and functions of lactate and lactylation have been extensively explored. Generated using Adobe Illustrator (Version 28.2). Abbreviations: APOC2 apolipoprotein C-II, DCs dendritic cells, FDG-PET ¹⁸F-fluorodeoxyglucose-positron emission tomography, FFA free fatty acids, K80-lac lysine 80 lactylation, MCT1 monocarboxylate transporter 1, MCT4 monocarboxylate transporter 4

Fig. 3

The overview of aberrant tumor lactate-related metabolism compared to physical conditions. In TME, cancer cells exhibit increased tumor glycolysis to meet their high energy demands and metabolic needs. This heightened glycolysis leads to elevated glucose consumption, resulting in excess lactate production and reduced ATP production in the cytoplasm. In normal cells, glycolysis involves ten steps, with the end product pyruvate entering the mitochondria for energy production via the TCA cycle. Besides participating in glucose metabolism, about 10% of the pyruvate is involved in other types of metabolism such as protein metabolism. Failure of pyruvate to enter the TCA cycle leads to decreased energy production compared to glucose molecules through altered glycolysis. Lactate in TME plays a crucial role in regenerating NAD+ molecules and directly join the TCA cycle under hypoxic conditions to sustain glycolysis and ATP production. In addition to glucose metabolism, increased glutaminolysis and lipogenic enzymes expression are also observed in TME. Generated using Adobe Illustrator (Version 28.2). Abbreviations: GLUT1/4 glucose transporter 1/4, TME tumor microenvironment

Fig. 4

Lactate is an intracellular and extracellular signal transducer of great significance. As it fulfills a role intracellularly, lactate boosts tumor malignancy in hypoxic environments through both HIF-1-dependent and HIF-1-independent pathways. Lactate not only fulfills its function intracellularly, but also serves as an extracellular ligand to GPR81. Extracellularly, GPR81/GPR132 imports lactate and subsequent signaling boosts its utilization, resulting to anti-tumor immunity impairment. Meanwhile, Lactate intensifies the crosstalk between metabolism and epigenetics by editing lactylation modification. Generated using Adobe Illustrator (Version 28.2). Abbreviations: bFGF basic fibroblast growth factor, ERK1/2 extracellular signal-regulated kinase 1/2, GLUT1/4 glucose transporter 1/4, GPR81 G-protein-coupled receptor 81, Kla lysine lactyl; NDRG3, N-Myc downstream-regulated gene family member 3, PHD prolyl hydroxylases, PKA protein kinase A, TAZ transcriptional co-activator with PDZ-binding motif, VHL Von Hippel Lindau tumor suppressor

Fig. 5

Histone/non-histone lactylation sites and their downstream genes following modification. Histone and non-histone lactylation sites and their downstream genes after modification are presented in the form of lactylation sites (downstream genes), with histone lactylation shown in brown and non-histone lactylation shown in green. Generated using Adobe Illustrator (Version 28.2). Abbreviations: AARS1, alanyl-tRNA synthetase 1; AK2 adenylate kinase 2, BCL2 B-cell lymphoma 2, CASP8 caspase 8, CBX3 chromobox 3, CD133 cluster of differentiation 133, CTGF connective tissue growth factor, CYR61 cysteine-rich protein 61, eEF1A2 elongation factor 1 alpha 2, FDX1 ferredoxin 1, GPI glucose-6-phosphate isomerase, HK1 hexokinase 1, HK2 hexokinase 2, IDH3G isocitrate dehydrogenase (NAD+) 3 gamma, LDHA lactate dehydrogenase A, METTL16 methyltransferase Like 16, MRE11 meiotic recombination 11, p21 p21^CIP1/WAF1, PDGFRβ platelet-derived growth factor receptor β, PKM pyruvate kinase M, PUMA p53 upregulated modulator of apoptosis, RUBCNL rubicon like autophagy enhancer, TEAD TEA domain transcription factor, XRCC1 X-ray repair cross-complementing 1, YTHDF2 YTH N (6)-methyladenosine RNA binding protein 2

Fig. 6

Lactic acid remodels variant cell populations in the TME. The TME consists of various cell types, including tumor, stromal, endothelial, and immune cells. Lactate impacts infiltrating immune cells by regulating their metabolism due to the Warburg effect, inhibiting the activation and proliferation of CD8 + T cells, natural killer (NK) cells, and dendritic cells, while promoting the immunosuppressive function of CD4 + CD25+ regulatory T (Treg) cells. Lactate also aids the polarization of macrophages towards an anti-inflammatory (M2-like) phenotype, supporting angiogenesis, tissue remodeling, and tumor progression. In cancer associated fibroblasts (CAFs), lactate production, driven by SIRT3/succinate-dependent HIF-1α activation, enhances BM remodeling, EMT, metastatic reprogramming, and treatment resistance. In endothelial cells, LDHB converts lactate to pyruvate, which enters the TCA cycle, influencing redox status, inducing reactive oxygen species (ROS), stabilizing HIF-1, and activating NF-κB signaling, which increases IL-8 and VEGF transcription. Thus, lactate significantly favors tumor progression, though detailed mechanisms remain unclear. Generated using Adobe Illustrator (Version 28.2). Abbreviations: bFGF, basic fibroblast growth factor; ERK1/2, extracellular signal eegulated kinase 1/2; GPR81, G-protein-coupled receptor 81; PHD, prolyl hydroxylases; PKA, protein kinase A; RUBCNL, Rubicon like autophagy enhancer; TAZ, transcriptional co-activator with PDZ-binding motif; VHL, Von Hippel Lindau tumor suppressor