Metabolic Pathways in Cancer Cell Biology

Within cancer cell biology, metabolic pathways extend beyond energy production to orchestrate biosynthetic and signalling events that underpin tumour growth and survival. While the classical Warburg effect emphasises enhanced aerobic glycolysis, recent insights highlight the concurrent utilisation and remodelling of mitochondrial pathways—most notably the tricarboxylic acid (TCA) cycle—to fuel anabolic demands and maintain redox balance. Aberrant accumulation of specific intermediates, or oncometabolites such as fumarate and succinate, drives epigenetic dysregulation, post-translational modifications and immunomodulatory signalling, thereby linking metabolic flux to gene expression, protein function and intercellular communication. This metabolic plasticity enables cancer cells to adapt to fluctuating microenvironmental conditions, promotes resistance to therapy and offers a spectrum of potential biomarkers and drug targets. Understanding how tumour cells balance glycolytic and oxidative pathways, engage alternative anaplerotic routes and exploit metabolite-mediated signalling is crucial for developing novel therapeutic interventions and precision diagnostics with global impact.

Research from Nature Portfolio

Recent studies have revealed that acute loss of fumarate hydratase leads to rapid remodelling of mitochondrial structure and the release of mitochondrial DNA into the cytosol, where it activates innate immune signalling through the cGAS–STING axis, unveiling a direct link between TCA disruption and antitumour immunity. Investigations into succinate dehydrogenase-deficient cells have further demonstrated a critical dependence on pyruvate carboxylase-mediated anaplerosis to replenish aspartate pools and sustain proliferation, identifying metabolic vulnerabilities that may be exploited therapeutically.

Metabolic Pathways in Cancer Cell Biology publication trend

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

Technical terms

TCA cycle: Also known as the Krebs or citric acid cycle, a mitochondrial pathway that oxidises acetyl-CoA to generate electron carriers and biosynthetic precursors.

Oncometabolite: A metabolite whose abnormal accumulation in cells promotes oncogenic signalling, epigenetic alterations or changes in the tumour microenvironment.

Succination: A chemical modification in which the TCA intermediate fumarate reacts with protein cysteine residues, altering protein function and redox balance.

Fumarate hydratase (FH): A mitochondrial enzyme that catalyses the conversion of fumarate to malate; its loss can lead to oncogenic metabolic remodelling.

Succinate dehydrogenase (SDH): An enzyme complex that oxidises succinate to fumarate and serves as complex II of the respiratory chain; its inactivation disrupts TCA flux and increases succinate levels.

Pyruvate carboxylase: An anaplerotic enzyme that converts pyruvate to oxaloacetate, replenishing TCA cycle intermediates when canonical flux is compromised.

References

1. Fumarate induces vesicular release of mtDNA to drive innate immunity. Nature (2023).
2. Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism. Nature Communications (2015).
3. Oncometabolites at the crossroads of genetic, epigenetic and ecological alterations in cancer. Cell Death & Differentiation (2024).
4. Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase-deficient renal cell carcinoma. Journal of Clinical Investigation (2023).
5. The Tricarboxylic Acid Cycle Metabolites for Cancer: Friend or Enemy. Research (2024).