Reducing calorie intake may enhance the body's immune response against cancer by changing how certain immune cells use energy, according to a study published in Nature Metabolism. Researchers from the Van Andel Institute and their collaborators investigated how dietary restriction affects the ability of CD8+ T cells—key immune cells involved in attacking tumors—in preclinical mouse models.
The study used a model where mice received half their usual calories for seven days before being induced with melanoma or breast cancer. The researchers found that this dietary restriction increased the number of tumor-fighting effector T cells and reduced the buildup of exhausted T cells within tumors. The anti-tumor effects were not seen in mice lacking functional T cells, underscoring the importance of these immune cells.
"By elevating ketone-driven energy pathways inside CD8+ T cells, dietary restriction steers them away from exhaustion and toward potent tumour-fighting states, unlocking stronger responses to immunotherapy in preclinical models," the authors stated.
Further analysis revealed that dietary restriction led to higher levels of ketone bodies—compounds produced when fat is broken down—in both blood and tumor tissue. These ketones fueled improved mitochondrial activity in T cells, which was necessary for their enhanced function. When T cells could not metabolize ketones, they became exhausted sooner and were less effective at controlling tumor growth under dietary restriction.
Acetyl-CoA, a molecule needed for optimal T cell function, was found at about twice the normal level in restricted-diet mice. The study suggests that increasing acetyl-CoA through ketone metabolism helps prevent terminal exhaustion of T cells during chronic stimulation.
The research also examined whether combining dietary restriction with PD-1 checkpoint inhibition—a form of cancer immunotherapy—would further boost anti-tumor immunity. Results showed that this combination promoted greater expansion of effector T cells and improved tumor control compared to either intervention alone.
Analyses of human tumor datasets indicated that gene signatures related to ketone body metabolism are present in effector-like exhausted CD8+ T cells across several solid cancers, though patient diet information was unavailable.
Researchers note that while these findings may help shape future nutritional guidelines alongside current cancer treatments, more studies are needed to determine safety and effectiveness in humans since prolonged caloric restriction may not be suitable for all patients.
