Most cancer cells depend on high blood glucose levels, which is a key factor in the development and progression of many cancers. Accordingly, diabetes and obesity caused by excessive calorie intake increase the risk of malignancy.

Conversely, calorie restriction exerts an anti-tumor effect. For instance, in 2010, an international group of researchers published a review of studies linking diet and cancer development. Their main conclusion: reducing caloric intake without compromising nutritional value helps prevent cancer.

The ketogenic diet is one way to reduce glucose intake while maintaining normal caloric levels. Several studies have shown that the keto diet not only suppresses tumor growth but also reduces inflammation within the tumor microenvironment. For example, a 2016 U.S. study demonstrated that a high-fat, high-protein diet boosted immunity and extended survival in mice with glioblastoma.

The immune system plays a central role in eliminating malignant cells. However, tumor cells escape immune surveillance by producing large amounts of PD-L1, a protein that suppresses immune activity to prevent autoimmune reactions. Modern immunotherapy with antibodies targets this protein, but clinical studies show that its effectiveness rarely exceeds 40%, depending on the cancer type. Researchers, therefore, aim to enhance this form of therapy.

Scientists from the U.S. and Taiwan hypothesized that a ketogenic diet could increase the effectiveness of cancer immunotherapy. They published their findings in 2022.

Study Design

The study evaluated the effects of the ketogenic diet on oncogenesis from three perspectives: in mice, in cell cultures, and at the genetic level.

Mice

Both healthy mice and those implanted with tumors were used. The animals were divided into feeding groups: standard diet or ketogenic diet. Mice with tumors received different treatments – immunotherapy alone, ketogenic diet alone, combination therapy, or no treatment (control). Researchers measured tumor growth rate, survival, and biochemical markers.

Cells

Two types of tumor cells were used – human and mouse – derived from melanoma, colorectal cancer, and breast cancer.
Cells were exposed to energy deprivation conditions: glucose was removed from the medium, ketone bodies were added, or an agent that induces the synthesis of energy-deficiency markers was introduced. The scientists examined how cancer cell viability changed under energy stress.

Genes

To understand the mechanisms by which the ketogenic diet affects cancer cells, researchers analyzed gene expression in tumor cells.

Study Results

The scientists found that the ketogenic diet not only deprives tumors of glucose but also activates anti-tumor immune pathways within cancer cells. This activation begins with increased production of type I interferon (IFN-I).

Ketogenic Diet Reduces Tumor Mass in Mice with Colon Cancer

The researchers first assessed the impact of the ketogenic diet on mice implanted with colon cancer cells. One group received a standard diet, the other a ketogenic diet, both with comparable caloric content. The experiment lasted 10 days.
Mice on the ketogenic diet showed lower PD-L1 levels – the protein that hides the tumor from immune attack. Lower PD-L1 levels correlated with smaller tumor mass. However, although tumor growth slowed, no mice survived.

Additionally, blood glucose levels were lower in mice on the ketogenic diet compared with those on the standard diet. The following findings were noted:

  • Caloric intake was nearly identical in both groups.
  • Blood glucose was lower in mice on the ketogenic diet.
  • Lower PD-L1 levels correlated with reduced tumor mass.
  • PD-L1 levels in immune cells were lower in the ketogenic diet group.

Image source: https://pmc.ncbi.nlm.nih.gov/articles/instance/8178223/bin/NIHMS1690825-supplement-1.pdf

Next, the scientists observed how glucose deprivation affects tumorigenesis in human and mouse cancer cells. Since PD-L1 plays a key role in immune evasion, they focused on its levels. Glucose deprivation sharply reduced PD-L1 expression, while glucose excess (hyperglycemia) increased it.

Ketogenic Diet Enhances the Effectiveness of Cancer Immunotherapy by Stimulating Interferon Synthesis in Tumor Cells

In the next series of experiments, the researchers evaluated the combined effect of the ketogenic diet and immunotherapy. They focused on changes in interferon levels, as the effectiveness of cancer immunotherapy is regulated by type I interferon signaling pathways.

The scientists again used mice implanted with colorectal cancer cells. One group received only immunotherapy, and the other – immunotherapy combined with a ketogenic diet.

As a result, survival in the first group was 42%, while in the combined treatment group it rose to 67%.

Analyzing tumor metabolism, the researchers discovered that tumor cells exposed to the ketogenic diet significantly increased type I interferon synthesis. Moreover, the activity of interferon-stimulated genes (ISGs) also rose. Consequently, more immune cells – T lymphocytes – infiltrated the tumor and better recognized cancer cells.

The results are shown in the figure below:

  • Vertical axis – survival rate;
  • Horizontal axis – days of the experiment;
  • Black curve – control group;
  • Blue curve – ketogenic diet only;
  • Green curve – immunotherapy only;
  • Red curve – combined immunotherapy plus ketogenic diet.

Image source: https://pmc.ncbi.nlm.nih.gov/articles/PMC8178223/figure/F2/

Drug Analogue of Ketogenic Diet Further Stimulates Interferon Synthesis and Increases Survival

In the final experiments, the researchers examined how the ketogenic diet stimulates IFN-I synthesis in tumor cells. They sought to evaluate the antitumor potential of drugs that could mimic the ketogenic effect and enhance immunotherapy outcomes.

Previous studies had shown that when cells experience glucose deprivation, they begin producing AMPK – a protein that regulates the body’s energy balance. For example, it activates genes affecting the brain and triggering hunger.

First, the scientists confirmed earlier findings that the ketogenic diet increases AMPK production in cells. Indeed, cells from mice on the ketogenic diet showed signs of glucose deprivation.

Then, they hypothesized that since the ketogenic diet stimulates the synthesis of both AMPK and type I interferon, AMPK might directly activate IFN-I production.

To test this, they analyzed the tumor cell genome and found that many genes were simultaneously associated with both interferon and AMPK pathways.

Further confirmation came from PCR analysis of IFN-I–associated genes and from experiments where cancer cells were treated with metformin to induce glucose starvation. These cells produced high levels of IFN-I and showed activation of interferon-stimulated genes. The researchers also noted that metformin stimulates AMPK synthesis.

In the final experiment, the scientists returned to mice, this time deprived of glucose by a substance similar to metformin, rather than a keto diet. Three groups of mice were implanted with tumors. The first group was treated with glucose deprivation alone. 13% of mice survived. In comparison, treatment with a keto diet alone slowed tumor growth, but not a single mouse survived, as discussed above. The second group of mice was treated with immunotherapy only. 40% of the mice survived. The third group of mice received a combination of immunotherapy and glucose deprivation. 73% of mice survived.

The results are shown below:

  • Vertical axis – survival rate;
  • Horizontal axis – days of the experiment;
  • Black curve – control group;
  • Blue curve – glucose deprivation (metformin analogue);
  • Green curve – immunotherapy only;
  • Red curve – combined immunotherapy plus glucose deprivation.

Image source: https://pmc.ncbi.nlm.nih.gov/articles/PMC8178223/figure/F7/

Conclusions

The ketogenic diet significantly increases survival in cancer treatment with immunotherapy.
Glucose deprivation induced by the ketogenic diet enhances antitumor immune mechanisms.
Survival improves even further when the ketogenic diet is replaced with drugs that mimic glucose deprivation.

References

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