Scientists have discovered a metabolic “Achilles heel” in relapsed lung tumours – a dependence on ketones for energy. These tumours, which have survived cancer therapy, become reliant on ketones for survival. What’s the link between lung cancer and ketones?
Cutting off the ketone energy supply causes the tumours to shrink and become vulnerable to conventional anti-cancer therapies. Moreover, a protein involved in ketone uptake may serve as a biomarker of early-stage lung cancer. This study opens the door for dietary manipulation being used as a tool to enhance cancer treatment efficacy.
Lung tumours can be tough customers. You can hit them with the most potent therapies science can offer, and yet somehow they survive. Poisoned and starved into silence, they lurk undetected, only to resurface and cause a relapse of the disease in survivors. These “resilient few” caught the attention of Dr Wat Leong Tam and his team at the Genomics Institute of Singapore. To understand why these cells don’t die, the team asked a simple question: where do the tumours get their energy from once their regular fuel runs out? Writing in the November 2025 edition of Cell Metabolism, they reported the discovery of a small population of undifferentiated “cancer stem cells”, deep within the tumour, that could burn ketones in order to survive.
Two engines, one purpose
Many cell types in the body function like hybrid electric vehicles – they can run on two types of energy. Hybrid cars run on electricity before seamlessly switching over to gasoline when the battery runs low. Similarly, many cells contain two independent “engine” options to power their cellular functions.
The primary energy source for all cells is glucose, but in times of famine, when energy supplies run low, some can switch to burning ketones. To do this, the body breaks into its fat supplies to provide the ketone energy it needs – this is how you lose weight on a ketogenic diet. Organs like the muscle, heart and brain, essential for survival, readily convert to burning ketones, whilst red blood cells and the liver don’t use them at all. Dr Tams’ group investigated whether lung tumours had this two-fuel metabolic flexibility – would supplying the tumours with ketones help or hinder the progression of the disease?
Putting the ketone brakes on lung cancer
The researchers started by switching the tumour cells growing in a petri dish from their dependence on glucose over to ketones. The tumor cells easily converted to the new fuel and actively grew, doubling within a month. Since the tumours could run off both fuels, starving them into submission with ketones would not work.
Dr Tam and the team realised that the relatively simple process of using ketones to power cell growth would be easier to disrupt than trying to block the widely available glucose uptake mechanisms. What would the lung cancer tumour cells do when a drug blocked ketone uptake and glucose was unavailable?
There are two proteins involved in ketone uptake; a transporter protein MCT-1 and its chaperone, CD147. The researchers inhibited the MCT-1/CD147 complex with an experimental drug, AZD3965. The drug, not yet approved by the FDA, is currently in clinical trials in the United Kingdom for patients with Burkitt’s lymphoma.
The results were clear. The tumours in the petri dish were now out of options – starved of energy, they shrank to just one fifth of their original size. However, it’s one thing to show this in a petri dish, but would it work in animals?
Ketones – fast and furious tumour fuel
Encouraged, the researchers replicated these experiments on mice with lung cancer. To switch the mice into ketosis, the researchers fed them a low-carbohydrate (Dr Atkins-style) diet. When the mice started breaking down their fat supplies into ketones, the tumours experienced turbocharged growth- like Vin Diesel at the wheel of his Charger. By adding the ketone-blocker, AZD3965, the team hit the brakes on further tumour development. No matter how big an engine you have, it can’t run without fuel.
As with the cell experiments, Tam and colleagues saw a dramatic difference in tumour growth. Ketone-producing mice given AZD3965 had tumours thirteen times smaller than keto-mice without AZD3965, or the glucose-fed controls. When the group knocked out the genes for MCT-1 and CD147, the gene-edited animals showed very little tumour development at all. These findings are certainly intriguing- could they point to a new direction using ketones in lung cancer treatments? Will this approach translate to humans?
What lies ahead?
The scientists caution that, as with all animal studies, it will be some years before we see them used in the clinic. There is still, they say, a lot of work to be done. For example, would researchers observe off-target side effects once they blocked MCT-1 and CD147? After all, these molecules have other transport roles in healthy human cells. The safety and efficacy of the drug in humans are currently being tested in clinical trials. One concern is that AZD3965 can cross the blood-brain barrier; researchers will need to ensure that it does not affect normal brain function.
A new biomarker for ketones detects lung cancer
In addition, the research provided some clinical evidence with an immediate practical benefit. The team noted that mice with higher levels of the CD147 protein in their blood experienced faster tumor growth.
This suggests that a simple CD147 blood test could one day help doctors detect more aggressive lung cancers early and begin treatment sooner – giving patients the best chance of recovery.
Don’t try it with diet – the Steve Jobs experience
Dietary approaches alone cannot control complex diseases such as cancer. In 2003, doctors diagnosed Apple founder Steve Jobs with a rare form of pancreatic cancer. Initially, he delayed having surgery and followed a fruitarian diet in a mistaken attempt to bring his cancer into remission.
By 2004, the tumour had grown, and he elected to have surgery. Tragically, the cancer had spread to his liver, and he passed away in 2011 at the age of 56.
Diet can clearly help or hinder the progression of the disease; it all depends on the type of fuel the cancer can live off. For example, the ketogenic diet has been associated with slower tumour growth in pancreas, prostate, colon, and brain cancers but boosted the growth of breast and skin cancer. Now we can add lung cancer to that list.
The way forward
Professor Tam’s research shows that eventually dietary manipulation might serve as a useful adjunct to enhance existing cancer therapies. The team’s results show a dramatic reduction in lung tumour growth – one can only imagine what adding an established anti-cancer therapy to this approach would do.
Research, as they say, is ongoing.
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.