Lactate Dehydrogenase Targeting in Cancer Metabolism

Tumour cells frequently adopt a high-glycolytic phenotype even under normoxic conditions, a phenomenon known as the Warburg effect. Central to this reprogramming is lactate dehydrogenase (LDH), which catalyses the reversible conversion of pyruvate to lactate and regenerates NAD+ to sustain elevated glycolytic flux. Two main isoforms, LDHA and LDHB, are differentially expressed in malignant and stromal compartments, contributing to lactate accumulation, acidosis and immunosuppression within the tumour microenvironment. Therapeutic inhibition of LDH activity can normalise metabolic fluxes, reduce lactate-driven immune evasion and force cancer cells towards oxidative phosphorylation, thereby sensitising them to chemotherapy, targeted agents or immunotherapy. Advances in structural biology have yielded potent NADH-competitive inhibitors and isoform-selective compounds, while genetic ablation models demonstrate that combined LDHA/LDHB suppression ablates fermentative glycolysis and limits hypoxic tumour growth. Emerging strategies explore LDH blockade in combination with immune checkpoint inhibitors, anti-angiogenic therapies or signal transduction inhibitors to overcome compensatory pathways. Challenges remain in achieving selectivity, minimising off-target effects and identifying predictive biomarkers for patient stratification. Nevertheless, LDH targeting represents a pivotal approach to exploit the metabolic vulnerabilities of cancer on a global scale.

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Lactate Dehydrogenase Targeting in Cancer Metabolism publication trend

The graph below shows the total number of articles in lactate dehydrogenase targeting in cancer metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Lactate dehydrogenase (LDH): Enzyme that interconverts pyruvate and lactate, regenerating NAD+ to support glycolysis.

Warburg effect: Metabolic shift in cancer cells favouring glucose fermentation to lactate despite sufficient oxygen.

Oxidative phosphorylation (OXPHOS): Mitochondrial process that generates ATP via the electron transport chain in the presence of oxygen.

Tumour microenvironment (TME): The complex milieu of cancer cells, stromal cells, immune infiltrates and extracellular factors surrounding a tumour.

Immune checkpoint blockade: Therapeutic antibodies that release inhibitory brakes on T cells to enhance antitumour immunity.

Isoform selectivity: The capacity of a drug to preferentially inhibit one enzyme variant (e.g. LDHA versus LDHB) over others.

References

1. Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models. Journal of Clinical Investigation (2024).
2. FOXQ1 promotes pancreatic cancer cell proliferation, tumor stemness, invasion and metastasis through regulation of LDHA-mediated aerobic glycolysis. Cell Death & Disease (2023).
3. Fibroblast growth factor pathway promotes glycolysis by activating LDHA and suppressing LDHB in a STAT1-dependent manner in prostate cancer. Journal of Translational Medicine (2024).
4. Lactate Dehydrogenases as Metabolic Links between Tumor and Stroma in the Tumor Microenvironment. Cancers (2019).
5. Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism. Journal of Biological Chemistry (2018).