Fasting enables natural killer cells to fight cancer better

Fasting, many diet gurus say, can help with weight loss and improve overall health. But what do scientists say? In general, they agree, although they prefer high-quality statements to blanket claims. For example, many scientists agree that fasting is associated with better cancer outcomes, but even these scientists remain skeptical. They demand mechanistic details.

Such details have emerged from a new study by researchers at Memorial Sloan Kettering Cancer Center (MSK). They found that the metabolism of natural killer cells (NK cells) was “rewired” in fasting mice. Ultimately, the NK cells improved their ability to survive the rigors of the tumor microenvironment and fought the cancer more effectively.

The MSK researchers presented their results in immunityin a paper titled “Fasting reshapes tissue-specific niches to enhance NK cell-mediated anti-tumor immunity.” The study’s lead author is postdoctoral fellow Rebecca Delconte, PhD, and the senior author is Joseph Sun, PhD, a researcher in the Immunology Program at MSK.

“During fasting, NK cells were redistributed from peripheral tissues to the bone marrow,” the authors of the article wrote. “NK cells in the spleen of fasting mice were metabolically rewired by increased concentrations of fatty acids and glucocorticoids, which increased fatty acid metabolism.”

The scientists observed that fasting-induced fatty acid oxidation was associated with increased expression of the enzyme CPT1A. To support this connection, the scientists deleted Cpt1a and found that this impaired NK cell survival and function.

“In parallel,” the scientists added, “the redistribution of NK cells to the bone marrow during fasting required the transport mediators S1PR5 and CXCR4. These cells were primed by an increased pool of myeloid bone marrow cells expressing interleukin (IL)-12, which enhanced IFN-γ production.”

The findings may help explain one of the mechanisms by which fasting may help the body fight off cancer — in addition to overall fat reduction and improved metabolism. And while more research is needed, the findings also suggest that fasting may be a strategy for improving immune responses to make immunotherapy more effective, the study authors note.

“Tumors are very hungry,” Sun emphasized. “They take up vital nutrients, creating a hostile environment that is often rich in lipids that are harmful to most immune cells. What we show here is that fasting reprograms these natural killer cells so they can better survive in this suppressive environment.”

For the study, mice with cancer were denied food for 24 hours twice a week, then allowed to eat freely between fasts. This approach prevented the mice from losing overall weight, the authors found. However, these fasting periods had a profound effect on NK cells.

Just like in humans, the mice's glucose levels dropped and free fatty acids increased. These are lipids released by fat cells that can serve as an alternative energy source when other nutrients are lacking, Delconte explained.

“During each of these fasting cycles, the NK cells learned to use these fatty acids as an alternative energy source to glucose,” she said. “This optimizes their cancer response because the tumor microenvironment contains a high concentration of lipids and they are now able to invade the tumor and survive better thanks to this metabolic training.”

Fasting also led to a redistribution of NK cells throughout the body. Many of the NK cells migrated to the bone marrow, where, thanks to fasting, they were exposed to high levels of an important signaling protein called interleukin-12. This primed the NK cells to produce more interferon-gamma, a cytokine that plays an important role in anti-tumor responses. At the same time, the NK cells in the spleen underwent a separate reprogramming that made them better able to use lipids as an energy source.

“When we put these two mechanisms together, we find that NK cells are primed to produce more cytokines in the tumor,” noted Delconte. “And through metabolic reprogramming, they are better able to survive in the tumor environment and they are specialized to develop enhanced anticancer properties.”

It is still unclear whether there are two separate populations of NK cells that are trained differently in different parts of the body, or whether the cells ultimately pass through both sites during their multi-week life cycle.

“That's the million-dollar question,” Sun noted. “And one that we've only just begun to answer with the cell labeling techniques we used in this study.”

Although the project did not examine human bone marrow samples, the researchers point out that blood samples from cancer patients show that fasting in humans leads to a reduction in freely circulating NK cells, just as they observed in mice.