Abstract. Cancer metabolism refers to the network of biochemical reactions that provide tumor cells with energy (ATP), molecular building blocks, and redox balance. Unlike most healthy tissues, many cancers favor aerobic glycolysis (the “Warburg effect”) and display striking flexibility in using glucose, amino acids (especially glutamine), lipids, and one-carbon units to sustain proliferation and survival under stress. Appreciating this metabolic plasticity clarifies why tumors resist therapy, how imaging like FDG-PET works, and where new treatments—including enzyme inhibitors and combination dietary approaches—may help.
Introduction: What do we mean by “metabolism” in cancer?
Cellular metabolism comprises thousands of enzymatic steps organized into pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and biosynthetic routes for nucleotides, lipids, and amino acids. In cancer, these pathways are reprogrammed by oncogenes (e.g., MYC, PI3K/AKT/mTOR) and loss of tumor suppressors (e.g., p53), as well as by microenvironmental cues like hypoxia and nutrient competition. The result is a state tailored for rapid growth, survival in hostile niches, and metastasis.
Figure: Dominant carbon flows in proliferating tumor cells (schematic).
The Warburg effect—and why mitochondria are not “broken”
Many tumors convert a large fraction of glucose to lactate even when oxygen is available. This “aerobic glycolysis” appears wasteful compared with OXPHOS, but it supports rapid ATP delivery, fuels biosynthesis through glycolytic side-paths (e.g., pentose phosphate pathway for ribose and NADPH), and keeps redox balance. Importantly, most cancers retain functional mitochondria. Mitochondria supply TCA intermediates for anabolism (via citrate for lipids and oxaloacetate for aspartate) and generate NADH/FADH2 used by the electron transport chain. The choice between glycolysis and OXPHOS is therefore contextual, not binary.
Fuel flexibility: glucose, glutamine, lipids, and one-carbon units
Glucose and the pentose phosphate pathway (PPP)
Glucose uptake is elevated in many cancers via transporters (GLUT1/3) and hexokinase anchoring at mitochondria. Diversion of glucose-6-phosphate into the PPP produces NADPH for antioxidant defense and ribose-5-phosphate for nucleotide synthesis. This underlies the clinical utility of FDG-PET imaging, which visualizes high glucose flux.
Glutamine as a carbon-nitrogen hub
Rapidly dividing cells are “glutamine addicted.” Glutaminase (GLS) converts glutamine to glutamate, which then becomes α-ketoglutarate to replenish (“anaplerose”) the TCA cycle. Glutamine also donates nitrogen for nucleotide and hexosamine pathways and participates in redox maintenance via glutathione.
Lipids: synthesis, scavenging, and β-oxidation
Tumors synthesize fatty acids de novo (e.g., via FASN) and also scavenge lipids from circulation and stromal cells. Lipids provide membranes, signaling lipids, and energy through β-oxidation. Some cancers toggle between lipogenesis and oxidation depending on nutrient availability and therapy pressure.
One-carbon metabolism and amino acids
Serine and glycine feed one-carbon units into folate and methionine cycles, supporting nucleotide synthesis and methylation. Enzymes such as SHMT and MTHFD are upregulated in several malignancies. Methionine/folate flux connects diet, epigenetics, and growth signals.
Oncogenic signaling rewires pathways
Metabolic states are controlled by signaling. PI3K/AKT/mTOR enhances glucose uptake and glycolysis; MYC upregulates ribosome biogenesis and glutamine catabolism; HIF-1 drives glycolytic gene expression and lactate export under hypoxia; p53 loss compromises mitochondrial integrity and antioxidant control. These programs coordinate to match nutrient processing to proliferation.
The tumor microenvironment: hypoxia, acidity, and crosstalk
Limited perfusion creates regional hypoxia, favoring HIF-mediated glycolysis and angiogenesis. Exported lactate (via MCT transporters) acidifies the microenvironment, shaping immune infiltration and drug uptake. Stromal fibroblasts and adipocytes can “feed” tumor cells with lactate, alanine, or fatty acids; immune cells and cancer cells compete for glucose and amino acids, affecting anti-tumor immunity.
Key idea: Cancer metabolism is not a single pathway but a system that flexes with genetics, nutrients, and therapy. This plasticity is why single-node interventions often show context-dependent responses.
Clinical translation: imaging, biomarkers, and vulnerabilities
FDG-PET exploits high glucose uptake, but newer tracers (e.g., for proliferation or amino acid transport) can reveal distinct dependencies. Serum lactate, LDH, and metabolomic signatures sometimes reflect tumor burden or aggressiveness. In select cancers, IDH1/2 mutations create an oncometabolite (2-hydroxyglutarate) that is both a biomarker and a drug target. Other actionable vulnerabilities include nucleotide synthesis, one-carbon metabolism, and oxidative stress buffering.
Therapeutic strategies targeting metabolism
Where therapies act
- Enzyme inhibitors: isocitrate dehydrogenase (IDH) inhibitors; glutaminase (GLS) inhibitors; dihydroorotate dehydrogenase (DHODH) inhibitors; fatty acid synthase (FASN) inhibitors under study.
- Transporters: blocking nutrient uptake (e.g., glucose or lactate transporters) may starve tumors or modulate the microenvironment.
- Redox targeting: disrupting glutathione or NADPH systems can sensitize cells to chemo- or radiotherapy by tipping oxidative balance.
- Combination approaches: pairing metabolic agents with targeted therapy, immunotherapy, or radiation to exploit synthetic lethality.
Because tumors adapt, metabolic therapy is rarely “one-size-fits-all.” Biomarker-guided use and rational combinations are crucial. Early trials show that some patients benefit when a dominant dependency is present (for example, IDH-mutant glioma). For others, transient rewiring can create therapeutic windows immediately after cytotoxic therapy, when biosynthetic demand is high and antioxidant defenses are strained.
Dietary patterns and lifestyle: what we know (and don’t)
Nutrition alters circulating fuels and hormones, which can influence tumor and host metabolism. Calorie control, low-glycemic patterns, and supervised fasting-mimicking protocols have been explored alongside therapy in select settings. Ketogenic approaches, rich in fats and lower in carbohydrates, aim to reduce glucose availability and insulin signaling while maintaining caloric sufficiency; responses are heterogeneous and patient-selection matters. Exercise can improve insulin sensitivity, mitochondrial function in normal tissues, and treatment tolerance.
Important: Dietary or supplement strategies should be individualized, medically supervised, and never substitute for evidence-based oncologic care. Co-morbidities (e.g., diabetes, cachexia), drug interactions, and cultural preferences must guide choices.
What this means for patients and families
- Expect heterogeneity: two tumors with the same name can behave differently metabolically; pathology and molecular profiling matter.
- Imaging is metabolic: FDG-PET detects glucose-hungry tissue; non-FDG tracers may be preferred in specific cancers.
- Side-effect management: fatigue, appetite changes, and weight loss have metabolic underpinnings; early dietetic support helps.
- Support normal tissues: sleep, physical activity, and symptom control preserve host metabolism and resilience during treatment.
Frontiers: precision metabolism
Future practice will likely integrate tumor genomics, metabolomics, and real-time physiological sensing. Non-invasive measures (e.g., circulating metabolites), functional imaging, and computational flux models could tailor therapy cycles and nutritional support. As more selective inhibitors and transporter modulators reach the clinic, precision metabolism may complement surgery, radiation, and systemic therapies to improve durability without undue toxicity.
Key takeaways
- Cancer cells repurpose core pathways to meet demands for ATP, building blocks, and redox balance; this is driven by oncogenic signaling and microenvironmental stress.
- The “Warburg effect” does not imply broken mitochondria; instead, tumors use both glycolysis and mitochondria dynamically.
- Major fuel streams—glucose, glutamine, lipids, and one-carbon units—are interlinked, enabling plasticity and therapy resistance.
- Clinical tools (FDG-PET, metabolite biomarkers) read out these fluxes; targeted drugs and rational lifestyle measures can, in select contexts, exploit vulnerabilities.
- Personalization and medical supervision are essential; metabolic interventions are most effective when integrated into comprehensive cancer care.
Suggested readings
- Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discovery.
- Vander Heiden MG, DeBerardinis RJ. Understanding the Warburg Effect. Science.
- Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression. Annual Review of Cancer Biology.
- Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metabolism.
- Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell.
This article is educational and does not replace personalized medical advice.