Targeting Metabolic Pathways in Cancer Cell Therapy

Tumour cells adapt their metabolism to sustain rapid proliferation and to evade immune surveillance, a phenomenon often termed metabolic reprogramming. Central to this reprogramming is an increased reliance on glycolysis, even in the presence of oxygen, alongside alterations in mitochondrial oxidative phosphorylation. Emerging strategies seek to exploit these metabolic dependencies by combining metabolic inhibitors with established cell therapies. By modulating nutrient uptake or by directly inhibiting key enzymes, it is possible to enhance the persistence and efficacy of adoptively transferred immune cells, to destabilise cancer stem cell populations and to overcome resistance mechanisms. Advances in single-cell analysis and in vivo imaging have revealed metabolic heterogeneity both within and between tumours, guiding the design of tailored therapeutic regimens. The resulting approaches span from direct blockade of glycolytic flux to the fine-tuning of immunometabolism, aiming to achieve durable anti-tumour responses with minimised off-target toxicity.

Research from Nature Portfolio

Recent studies have shown that transient inhibition of glycolysis can synergise with locoregional ablation to reshape T-cell differentiation. In preclinical models of breast cancer, combining a glycolytic inhibitor with microwave ablation drove the emergence of long-lived central memory CD8+ T cells, resulting in sustained tumour control and resistance to recurrence. This approach harnesses the metabolic checkpoint STAT-1 to promote peripheral T-cell remodelling and has laid the groundwork for forthcoming clinical evaluation of metabolic priming in conjunction with minimally invasive therapy. In another foundational study, targeting glycolysis in aggressive triple-negative breast cancer cells with a glucose analogue significantly curtailed invasion, reversed features of mitochondrial dysfunction and depleted the subpopulation of cells exhibiting stem-like properties. This work demonstrated that metabolic intervention alone can reduce tumour aggressiveness and suggested broader applications across diverse cancer types.

Targeting Metabolic Pathways in Cancer Cell Therapy publication trend

The graph below shows the total number of articles in targeting metabolic pathways in cancer cell therapy across all publications each year (not limited to Nature Index journals).

Technical terms

Glycolysis: Anaerobic breakdown of glucose to pyruvate, generating ATP rapidly and supporting biosynthetic precursors in cancer cells.

Oxidative phosphorylation (OXPHOS): Mitochondrial process using the electron transport chain to produce ATP efficiently from nutrients under aerobic conditions.

2-Deoxy-d-glucose (2-DG): A glucose analogue that inhibits hexokinase and impedes glycolytic flux, used experimentally to starve cells of energy.

Metabolic heterogeneity: Variation in metabolic pathway usage among different tumour cells or within distinct regions of the same tumour.

Cancer stem cell (CSC): A subpopulation of tumour cells with self-renewal capacity and heightened resistance to conventional therapies.

References

1. Glycolysis inhibition induces anti-tumor central memory CD8+T cell differentiation upon combination with microwave ablation therapy. Nature Communications (2024).
2. 2-Deoxy-D-Glucose inhibits aggressive triple-negative breast cancer cells by targeting glycolysis and the cancer stem cell phenotype. Scientific Reports (2019).
3. Metabolic heterogeneity in TNBCs: A potential determinant of therapeutic efficacy of 2-deoxyglucose and metformin combinatory therapy. Biomedicine & Pharmacotherapy (2023).
4. Aurora kinase A/AURKA functionally interacts with the mitochondrial ATP synthase to regulate energy metabolism and cell death. Cell Death Discovery (2023).
5. The troglitazone derivative EP13 disrupts energy metabolism through respiratory chain complex I inhibition in breast cancer cells and potentiates the antiproliferative effect of glycolysis inhibitors. Cancer Cell International (2024).