Discovery of a Metabolic Vulnerability in Relapsed Lung Tumours

Dependence on Ketones for Energy

Recent research has uncovered a significant metabolic “Achilles heel” in relapsed lung tumours: their reliance on ketones for energy. Tumours that have endured cancer treatment exhibit a strong dependence on ketones for survival. Cutting off their ketone supply leads to tumour shrinkage and increases their susceptibility to traditional anti-cancer therapies. Furthermore, a protein associated with ketone uptake may act as a biomarker for early-stage lung cancer, suggesting that dietary modifications could enhance cancer treatment effectiveness.

The Resilience of Lung Tumours

Lung tumours often prove to be resilient adversaries. Despite the most advanced therapies, they may survive and eventually cause a relapse in patients. This phenomenon caught the attention of Dr. Wat Leong Tam and his research team at the Genomics Institute of Singapore. To understand the survival mechanisms of these tumours, the team investigated their energy sources after conventional fuel supplies were depleted. In a study published in the November 2025 edition of Cell Metabolism, they identified a small population of undifferentiated “cancer stem cells” within the tumour that can utilize ketones for energy.

Metabolic Flexibility in Lung Tumours

The Dual Fuel System

Cells in the body can operate like hybrid vehicles, using two types of energy sources. Typically, glucose serves as the primary energy source, but when it is scarce, some cells can switch to burning ketones. This metabolic flexibility allows the body to draw on fat supplies to produce ketones, a process leveraged in ketogenic diets. While organs like muscles, the heart, and the brain can easily adapt to ketone metabolism, others, such as red blood cells and the liver, do not utilize them. Dr. Tam’s team explored whether lung tumours possess this dual-fuel capability and how supplying them with ketones would affect disease progression.

Disrupting Ketone Utilization in Tumours

The researchers initially shifted tumour cells in a petri dish from glucose reliance to ketone utilization. The cells adapted quickly, doubling in size within a month, demonstrating that simply depriving them of glucose wouldn’t hinder their growth. Recognizing the potential to disrupt ketone metabolism, Dr. Tam and his team explored the inhibition of the MCT-1/CD147 protein complex involved in ketone uptake using the experimental drug AZD3965, which is currently in clinical trials for other cancers.

Experimental Results and Implications

Effects on Tumour Growth in Mice

Encouraged by their findings, the researchers conducted experiments on mice with lung cancer. By placing the mice on a low-carbohydrate diet to induce ketosis, they observed accelerated tumour growth. However, administering AZD3965 effectively halted further tumour development. The results were striking: ketone-producing mice treated with AZD3965 exhibited tumours that were thirteen times smaller than those of untreated keto-mice or mice fed glucose.

Potential for Future Treatments

The research raises intriguing possibilities for new lung cancer treatments. However, the scientists caution that while the results are promising, translating these findings to human applications will take time. Further studies are needed to assess the potential side effects of blocking MCT-1 and CD147, as these proteins play roles in healthy human cells, including the brain.

Identifying a New Biomarker for Lung Cancer

CD147 as a Potential Indicator

In addition to the primary findings, the research revealed that higher levels of the CD147 protein in the blood of mice correlated with faster tumour growth. This observation suggests that a simple blood test for CD147 could enable earlier detection of aggressive lung cancers, allowing for timely intervention and improving patient outcomes.

Understanding Dietary Impacts on Cancer

The Complexity of Dietary Approaches

While dietary strategies can influence cancer progression, they cannot singularly control complex diseases like cancer. A historical example is the case of Steve Jobs, who delayed surgical treatment for pancreatic cancer in favor of a fruitarian diet, ultimately leading to tragic consequences.

Diet and Tumour Growth

Research indicates that ketogenic diets may slow tumour growth in certain cancers, such as those of the pancreas and brain, while potentially accelerating others, like breast and skin cancers. This study adds lung cancer to the list of types potentially influenced by dietary composition.

Conclusion: Future Directions in Cancer Research

Implications for Treatment Strategies

Professor Tam’s research underscores the potential for dietary manipulation to serve as a complementary strategy to enhance existing cancer therapies. The dramatic reductions in lung tumour growth observed in this study prompt further exploration of how integrating established anti-cancer treatments with dietary approaches could improve patient outcomes. Ongoing research will continue to investigate these promising avenues.

Reference

Wu Z, et al. Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet–induced therapeutic vulnerability in lung cancer. Cell Metab. 2025;37(11):2233-2249.e9.