Popular supplement creatine supercharges critical immune cells fighting cancer

Creatine, the organic acid that is popularly taken as a supplement by athletes and bodybuilders, supercharges a critical class of immune cells that activate and prepare the body's key cancer-fighters, according to new UCLA research.

The study, conducted in mouse models and human cells and published in iScience, builds directly on earlier work from the same lab showing that creatine powers killer T cells in their battle against tumors. Now, the team has discovered that creatine also fuels dendritic cells, specialized immune cells that capture tumor fragments and direct killer T cells to attack. 

Most approved cancer immunotherapies work by targeting killer T cells directly, yet only about 20%-40% of patients respond to them. Bolstering the dendritic cells that train and activate T cells could potentially offer a way to bring the benefits of immunotherapy to more patients.

Immunotherapy has shown remarkable promise, but it only works for a subset of patients. What this study shows is that creatine doesn't just help the T cells fighting cancer - it also energizes the entire infrastructure supports and guides them. That makes creatine a promising supplement to holistically support the immune response that modern immunotherapies depend on."

Lili Yang, study's senior author, professor of microbiology, immunology and molecular genetics and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA

The researchers began by examining which metabolic genes were most active in dendritic cells that had infiltrated tumors in mice. They found that the gene encoding the creatine transporter - a protein that pulls creatine inside cells - was markedly elevated in dendritic cells inside tumors compared to those in healthy tissue.

To find out why, the team grew and studied dendritic cells that had been engineered to lack the creatine transporter entirely. These cells showed impaired survival, reduced activation and a weakened ability to prime T cells to mount a response against tumors. When creatine-deficient dendritic cells were grown alongside T cells in a lab dish, those T cells divided less and produced fewer of the signaling molecules needed to fight cancer.

The team then tested the opposite intervention: Instead of reducing creatine levels, the researchers increased them to see whether this could enhance the dendritic cells' function. Giving daily creatine injections to mouse models of melanoma significantly slowed tumor growth and boosted both the abundance and the activation of tumor-infiltrating dendritic cells. Creatine-treated dendritic cells also produced higher levels of chemical signals that draw additional immune cells into the tumor.

Using metabolomics analyses, the researchers found that creatine supplementation raised intracellular ATP levels in dendritic cells - ATP is the energy currency cells use to power virtually every function - and sustained the key inflammatory signaling pathways needed for activation. Like a battery storing and releasing excess energy on demand, creatine helps dendritic cells maintain stable energy levels even when competing with fast-growing tumor cells for nutrients.

The researchers also tested creatine's effects on human dendritic cells. Creatine treatment enhanced the activation of human monocyte-derived dendritic cells, which are often used in dendritic cell cancer vaccines, and improved their ability to stimulate human T cells against a cancer-associated target. The findings suggest that incorporating creatine during the manufacturing of dendritic cell vaccines may boost their therapeutic potency. 

"The potential we see here is that creatine could be used in two complementary ways: as a supplement to enhance the immune response of patients already receiving immunotherapy, and as a tool to improve the quality of dendritic cell-based vaccines before they're administered," said James Elsten-Brown, a co-first author and graduate student in Yang's lab. 

Together, the findings point to creatine as a potential tool for strengthening the immune system's anti-cancer response at multiple levels, including the cells that detect the threat and set the response in motion.

"Understanding how to metabolically support dendritic cells is about supporting the entire anti-tumor response, not just the killer T cells at the end of it," said Elliot Kang, a co-first author of the study and former undergraduate student researcher in Yang's lab.

The researchers emphasize that while the findings are scientifically promising, this study was conducted in cells and mice, not patients, and no dietary or medical recommendations should be drawn from it. Although creatine monohydrate has been widely used as a supplement for decades and is generally considered safe at recommended doses, anyone undergoing cancer treatment should consult their doctor before adding any supplement to their routine. 

Next, the team hopes to collaborate with physicians on prospective clinical trials that could test whether creatine supplementation improves outcomes in patients receiving immunotherapy.

The experimental strategies described in this study have not been tested in humans or approved by the Food and Drug Administration as safe and effective for use in humans.

Funding for the study was provided by a UCLA Broad Stem Cell Research Center Rose Hills Foundation Innovator Grant; the UCLA Health Jonsson Comprehensive Cancer Center and UCLA Broad Stem Cell Research Center Ablon Scholars Program; and a Magnolia Council Senior Investigator Grant Award and a fellowship from the Tower Cancer Research Foundation. 

This newly identified potential therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California.