Metabolic Therapy Strategies in Cancer Management

Cancer cells reprogramme their energy metabolism to support rapid growth and survival, most notably by upregulating aerobic glycolysis and glutaminolysis even in the presence of oxygen. These adaptations create specific vulnerabilities that can be exploited therapeutically. Metabolic therapy strategies encompass dietary interventions such as ketogenic diets, calorie restriction and fasting-mimicking regimens that shift systemic fuel usage from glucose to ketone bodies, which many tumours cannot efficiently metabolise. Complementary pharmacological approaches target key enzymes in glycolytic and glutaminolytic pathways, including hexokinase, lactate dehydrogenase and glutaminase, or inhibit signalling cascades downstream of PI3K–AKT–mTOR to disrupt tumour bioenergetics and biosynthesis.

Dietary metabolic therapy aims to increase substrate competition in the tumour microenvironment, normalise systemic insulin and growth factor levels, and create a metabolic priming baseline that sensitises malignant cells to cytotoxic agents. Clinically, the glucose–ketone index has emerged as a real-time biomarker of compliance and therapeutic ketosis, guiding personalised adjustment of macronutrient ratios. Pharmacological metabolic modulators—such as biguanides, specific enzyme inhibitors and repurposed drugs—are studied both as monotherapies and in combination with standard modalities like radiotherapy, chemotherapy and targeted agents to overcome resistance.

Recent advances have highlighted immunometabolic crosstalk, showing that dietary and pharmacological perturbations of tumour metabolism can enhance antitumour immunity. By reducing tumour-associated hypoxia and modulating myeloid cell function, metabolic interventions can improve the efficacy of immune checkpoint blockade. Together, these approaches offer a multi-pronged blueprint for global translation, with emerging frameworks for observational and interventional trials across diverse cancer types.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Metabolic Therapy Strategies in Cancer Management publication trend

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

Technical terms

Glycolysis: Metabolic pathway converting glucose to pyruvate with net ATP production.

Glutaminolysis: Catabolism of glutamine to fuel tricarboxylic acid cycle intermediates and nucleotide synthesis.

Ketogenic diet: High-fat, low-carbohydrate dietary regimen that elevates circulating ketone bodies while lowering glucose.

Ketone bodies: Alternative energy substrates (acetoacetate, β-hydroxybutyrate, acetone) generated by hepatic fatty acid oxidation.

Glucose–ketone index (GKI): Ratio of blood glucose to ketone concentration, used as a biomarker of metabolic state.

Metabolic priming: Preconditioning of systemic and tumour metabolism to enhance susceptibility to subsequent therapies.

Immune checkpoint blockade: Cancer immunotherapy targeting inhibitory receptors or ligands (e.g. PD-1/PD-L1) to restore T-cell-mediated tumour eradication.

References

1. Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma. BMC Medicine (2024).
2. Ketogenic diet in the treatment of cancer – Where do we stand?. Molecular Metabolism (2019).
3. Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer (2011).
4. Ketogenic diet and ketone bodies enhance the anticancer effects of PD1 blockade. JCI Insight (2021).
5. Mechanisms by Which Low Glucose Enhances the Cytotoxicity of Metformin to Cancer Cells Both In Vitro and In Vivo. PLOS ONE (2014).