Timing Nutrition to Boost Antitumor Immunity

Researchers are increasingly recognizing the effects of fasting—or calorie-restricted diets that emulate fasting—on metabolism.¹ Metabolic processes influence the availability of molecules like glucose for cancer cells, and reducing such nutrients can effectively regulate cancer cell growth and survival. Studies have indicated that dietary interventions can influence cancer outcomes in mouse models.² Furthermore, small-scale clinical trials have demonstrated that people who underwent fasting alongside cancer therapy were more responsive to drugs and had improved antitumor immunity.³

In a study that further corroborated these observations, scientists found that cyclic fasting in mice improved their antitumor responses mediated by natural killer (NK) cells.⁴ The results, published in Immunity, highlight how dietary restriction could enhance the efficacy of cancer immunotherapy.

To test the effects of fasting, the researchers withheld food from tumor-bearing mice for one day, then let them eat freely for two days, repeating this pattern for three weeks. This intermittent fasting regimen resulted in reduced blood glucose, and elevated free fatty acids, which are used as an alternate energy source by cells. Furthermore, mice on this diet for three weeks had smaller tumor volumes and reduced metastases compared to control mice.

“There were a number of studies looking at how fasting was affecting different facets of the immune system and also affecting tumor cells and systemic responses,” said study author Rebecca Delconte, a cancer immunologist at Memorial Sloan Kettering Cancer Center. “But no one had really looked into whether NK cells were playing a part.” This was an important knowledge gap as NK cells can recognize and attack stressed cells such as tumor cells and limit their growth.⁵

To assess whether NK cells were involved in antitumor response generated by fasting, Delconte and her team depleted these cells using antibodies. They observed that fasted mice with intact NK cells had smaller tumor sizes compared to fasted mice lacking NK cells.

This was a striking result, said Delconte. “I was like—I think I also need to start fasting!”

NK cell populations are present in different sites such as the spleen, blood, and bone marrow.⁶ Since NK cells from different tissues exhibit different characteristics, the researchers analyzed the impact of fasting on NK cells in each system.

The team focused on splenic NK cells first. While a majority of other immune cell populations decreased in the spleen of fasted mice, NK cells did not show a similar cell death. The researchers investigated how NK cells survived and found that NK cells in fasted mice took up fatty acids in the absence of glucose. RNA sequencing of splenic NK cells in fasted mice showed increased expression of genes involved in fatty acid metabolism, indicating that fasting rewires splenic NK cells to use fatty acids as an energy source and survive even during times of glucose withdrawal. The team similarly observed increased fatty acid uptake in NK cells within the tumors of fasted mice.

Next, the team investigated NK cell populations in the bone marrow of fasted mice. RNA sequencing of this NK cell population revealed increased expression of genes involved in the signaling pathway of interleukin (IL)-12, a cytokine that mediates NK cells’ cytotoxic function. Consistent with this, they also observed increased IL-12 concentration in the bone marrow of fasted mice. Researchers have previously reported that IL-12 stimulates the secretion of another cytokine, interferon gamma (IFN-γ), an important mediator of anti-tumor response.⁷ Consistent with this, Delconte and her team found increased IFN-γ secretion from NK cells in the bone marrow of fasted mice.

When the fasted mice returned to a daily feeding schedule, the researchers found that the IFN-γ-secreting NK cell populations were redistributed from the bone marrow to the spleen. Compared to well-fed mice, the splenic NK cells of the previously fasted mice secreted more IFN-γ, indicating that fasting primes both splenic and bone marrow NK cells to secrete tumor-fighting cytokines.

“[The findings] give us a little bit more clarity around what is potentially happening when patients are using fasting in combination with their cancer therapy,” said Delconte.

A clinical trial with 101 participants indicated that exposing people with cancer to a combination of standard antitumor therapies and a five-day regimen of fasting-mimicking diet improved their antitumor immunity, although effects on cancer progression were not evaluated.⁸ Profiling these patients’ immune cells revealed that the response was partly mediated by an increase in NK cell populations.

“There is a good chance that this is something that is translatable [to humans],” said Delconte. But such fasting-based approaches must be practiced under appropriate medical supervision to prevent weight loss, she cautioned.

This is a very elegant study, said May Daher, a physician-scientist with expertise in adoptive NK cell therapy at the MD Anderson Cancer Center, who wasn’t involved in the study. A fasting-based strategy would be easy to implement in a clinical trial and is worth trying, she said. “It would be exciting to try to combine NK cell therapies with some form of intermittent fasting strategy to enhance NK cell function and activity, [to] treat patients with cancer.”

Going forward, Delconte’s team hopes to achieve enhanced antitumor immunity by targeting the pathways activated by fasting, without requiring the patients to fast. “If we can target those pathways outside of fasting to improve the NK cell response, that would be the overall goal of what we're trying to achieve.”

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