Cancer Metabolism & Immunometabolism: How Cancer Cells Rewire Energy to Outsmart the Body

 

Introduction: Energy — The Secret Language of Cancer

All living cells depend on energy to survive. For healthy cells, this energy production follows an efficient and well-regulated process. But cancer cells live by different rules. They reprogram their metabolism to meet their insatiable demand for energy and raw materials, even when nutrients or oxygen are scarce.

This phenomenon, called metabolic reprogramming, is one of the defining features of cancer physiology. It not only fuels tumor growth but also influences how immune cells behave around tumors — an emerging field known as immunometabolism [1].

Understanding how cancer manipulates these pathways helps researchers develop more effective therapies and dietary strategies to starve cancer without harming normal tissues.

The Warburg Effect: How Cancer Redefines Energy Production

In the 1920s, scientist Otto Warburg observed something unusual: cancer cells prefer to generate energy through glycolysis, even when oxygen is available — a far less efficient process than oxidative phosphorylation. This became known as the Warburg effect [2].

In normal physiology, cells use glycolysis only when oxygen is low, because it produces just 2 ATP molecules per glucose molecule. However, cancer cells favor glycolysis because it provides metabolic flexibility — producing energy quickly and generating intermediate molecules needed for cell division and growth [3].

Why the Warburg Effect Matters

• It allows cancer cells to survive in low-oxygen (hypoxic) environments.

• It creates an acidic microenvironment that helps break down nearby tissues.

• It supports the production of amino acids, lipids, and nucleotides essential for rapid cell proliferation.

Essentially, cancer metabolism isn’t “inefficient” — it’s optimized for survival under stress

Metabolic Pathways That Power Cancer

Cancer doesn’t rely on a single energy source. It adapts to whatever nutrients are available in its surroundings.

a) Glucose Metabolism

Cancer cells increase glucose uptake by overexpressing transporters like GLUT1. The excess glucose fuels glycolysis and supports biosynthesis [4].

Enzymes like hexokinase II and pyruvate kinase M2 (PKM2) are often overactive, helping redirect glucose metabolites toward pathways that promote growth rather than just energy.

b) Glutamine Addiction

Many tumors are “addicted” to the amino acid glutamine, which provides carbon and nitrogen for building proteins, nucleotides, and antioxidants. This process, called glutaminolysis, supports both energy and redox balance [5].

Without glutamine, many cancer cells cannot survive — making it a promising target for metabolic therapies.

c) Lipid Metabolism

Cancer cells also increase fatty acid synthesis and uptake. Fatty acids are needed for membrane formation and act as energy reserves. Enzymes like fatty acid synthase (FASN) are often overexpressed in aggressive tumors [6].

The Metabolic Tug-of-War in the Immune System

The link between metabolism and immunity forms the basis of immunometabolism — a rapidly expanding field in human physiology.

Immune cells, just like cancer cells, depend on specific metabolic pathways to function. However, the tumor microenvironment often starves immune cells of the nutrients they need, effectively silencing the body’s defense system.

a) T-Cell Energy Crisis

Cytotoxic T-cells (the “soldiers” that attack cancer) rely on glucose to produce cytokines and kill tumor cells. But in the tumor microenvironment, cancer cells consume most of the glucose, leaving T-cells metabolically exhausted [7].

Low glucose means T-cells can’t maintain their activity, leading to immune evasion.

b) Macrophages: Friends or Foes?

Macrophages in tumors can exist in two forms:

• M1 macrophages, which kill cancer cells (pro-inflammatory)

• M2 macrophages, which promote tumor growth (anti-inflammatory)

The TME’s hypoxic, lactic-acid–rich environment pushes macrophages toward the M2 state, helping the tumor survive [8].

c) Lactic Acid: The Silent Immunosuppressor

The acid produced by glycolysis (lactic acid) accumulates in the tumor environment, suppressing immune responses and preventing dendritic cells from activating T-cells. This metabolic “fog” allows cancer to hide in plain sight [9].

How Cancer Metabolism Drives Therapy Resistance

Cancer’s ability to rewire its energy sources also explains why many treatments fail over time.

• Chemotherapy resistance: Cancer cells increase antioxidant production (via glutamine and NADPH) to neutralize reactive oxygen species (ROS) generated by chemotherapy [10].

• Targeted therapy resistance: When one pathway is blocked (like glycolysis), tumors can switch to others, such as fatty acid oxidation.

• Immunotherapy resistance: Nutrient deprivation and lactic acid buildup in the TME prevent immune cells from working effectively, reducing the success of checkpoint inhibitors.

This metabolic flexibility is one of the reasons cancer is so difficult to eliminate completely.

Targeting Cancer Metabolism: New Therapeutic Frontiers

Modern oncology is now moving toward metabolic therapy — drugs and strategies that disrupt cancer’s unique energy systems.

a) Inhibiting Glycolysis

Drugs that block key glycolytic enzymes like hexokinase or LDH-A can reduce energy supply to tumors. However, balancing toxicity to normal cells remains a challenge.

b) Starving Glutamine-Dependent Tumors

Compounds such as CB-839 inhibit glutaminase, cutting off the tumor’s access to glutamine metabolism [11]. Early trials show promise in specific cancers like triple-negative breast cancer and renal carcinoma.

c) Restoring Immune Metabolism

New immunotherapies aim to reprogram immune cells metabolically — for instance, increasing mitochondrial efficiency in T-cells so they can survive nutrient-poor environments [12].

d) Diet and Lifestyle Approaches

Emerging research suggests that ketogenic diets (low carbohydrate, high fat) may slow tumor growth by limiting glucose availability. While still under investigation, such metabolic interventions highlight how deeply cancer is tied to the physiology of energy [13].

Future of Immunometabolic Research

The next generation of cancer research is merging physiology, metabolism, and immunology. Key focus areas include:

• Mapping metabolic “fingerprints” of different cancers.

• Developing nanoparticle-based drug delivery that targets metabolic enzymes.

• Designing dual therapies that boost immune metabolism while blocking cancer’s.

• Using AI and metabolic imaging to monitor treatment response in real time.

This systems-level understanding may eventually allow doctors to customize treatment based on each tumor’s unique metabolic code.

Conclusion: Cancer’s Energy Strategy — A Double-Edged Sword

Cancer metabolism is a masterclass in physiological adaptation. By rewriting the rules of energy, cancer cells gain speed, flexibility, and survival advantages — but these same differences make them vulnerable to targeted disruption.

The more we understand cancer’s metabolism and its interaction with the immune system, the closer we get to therapies that not only kill tumors but also empower the body’s natural defenses.

Just as the Tumor Microenvironment revealed cancer as an ecosystem, cancer metabolism reveals it as a living engine — powerful, adaptive, and increasingly predictable.

References

1. Pavlova, N. N., & Thompson, C. B. (2016). The Emerging Hallmarks of Cancer Metabolism. Cell Metabolism, 23(1), 27–47.

2. Warburg, O. (1956). On the origin of cancer cells. Science, 123(3191), 309–314.

3. Liberti, M. V., & Locasale, J. W. (2016). The Warburg Effect: How Does it Benefit Cancer Cells? Trends in Biochemical Sciences, 41(3), 211–218.

4. Zhao, Y., et al. (2013). GLUT1 overexpression in tumors: mechanisms and therapeutic potential. Cancer Letters, 337(2), 174–181.

5. Altman, B. J., et al. (2016). Glutamine metabolism in cancer: therapeutic potential and complexity. Nature Reviews Cancer, 16(12), 619–634.

6. Röhrig, F., & Schulze, A. (2016). The multifaceted roles of fatty acid synthesis in cancer. Nature Reviews Cancer, 16(11), 732–749.

7. Chang, C. H., et al. (2015). Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell, 162(6), 1229–1241.

8. Colegio, O. R., et al. (2014). Functional polarization of tumor-associated macrophages by lactic acid. Nature, 513(7519), 559–563.

9. Fischer, K., et al. (2007). Inhibitory effect of tumor cell–derived lactic acid on human T cells. Blood, 109(9), 3812–3819.

10. DeNicola, G. M., et al. (2011). Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature, 475(7354), 106–109.

11. Gross, M. I., et al. (2014). Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Molecular Cancer Therapeutics, 13(4), 890–901.

12. Scharping, N. E., et al. (2021). Restoring T cell metabolism for immunotherapy of cancer. Nature Reviews Cancer, 21(6), 435–450.

13. Weber, D. D., et al. (2020). Ketogenic diet in cancer therapy: molecular mechanisms and clinical implications. International Journal of Molecular Sciences, 21(24), 9445.

Article By: 

Brian Opiyo-KRCHN (Kenya Medical Training College), BScN (AMREF International University)