A new study reveals how bacteria in the gut can help determine whether the amino acid asparagine from the diet will feed tumor growth or activate immune cells against the cancer, according to researchers at Weill Cornell Medicine. This casts the gut microbiome, comprising the trillions of microorganisms that live in the intestine, as a central player in the body's response to cancer and to modern cancer treatments like immunotherapies.
The findings , published, Jan. 2 in Cell Microbe and Host, could lead to a novel cancer treatment approach and monitoring strategy—instead of targeting tumors directly, clinicians may one day be able to reshape the gut microbiome or diet to starve tumors while supercharging immune cells.
"Our study suggests that we need to think about how the interplay of diet, gut microbiota and tumor-infiltrating immune cells could affect cancer growth and response to therapy. We can't overlook this key level regulation," said Dr. Chunjun (CJ) Guo , the Halvorsen Family Research Scholar in Metabolic Health and associate professor of immunology at Weill Cornell, who co-led the study.
This research is the result of a close collaboration with co-corresponding authors Dr. David Artis , director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Michael Kors Professor in Immunology, and Dr. Nicholas Collins , assistant professor of immunology and a member of the Friedman Center for Nutrition , both at Weill Cornell.
Microbes Deplete Intestinal Asparagine
The researchers first established in mouse models with human gut microbiota that some bacteria could deplete amino acids and affect tumor progression. Next, they focused on asparagine, an amino acid that supports protein synthesis and promotes cell survival. Both cancer cells in the nutrient-poor environment inside tumors and CD8+ T cells, the cytotoxic immune cells that directly attack and destroy tumor cells, require the amino acid to be active.
To understand the impact of microbiota asparagine metabolism, the team worked with Bacteroides ovatus, a common gut bacterium with a gene called bo‑ansB, which encodes an enzyme that breaks down asparagine. Using mouse models, the researchers showed that when the bo‑ansB gene is present, B. ovatus consumes more asparagine in the gut, so less of it is absorbed into the bloodstream and delivered to tumors.
When the bo‑ansB gene was knocked out, the bacteria was not able to deplete asparagine in the intestine, so more of the amino acid reached the blood circulation and tumor. This demonstrated that the bacteria control the overall level of asparagine that leaves the gut and shapes the battlefield that tumors and immune cells share.
In mouse models of colorectal cancer fed extra dietary asparagine, bacteria with bo-ansB helped tumors grow. In mice with the bo‑ansB‑deleted bacteria, the same asparagine‑rich diet had the opposite effect: more asparagine reached the tumor and was taken up by CD8+ T cells. This triggered the immune cells into a "stem-like" state associated with long-lasting, effective anti-tumor responses. In contrast, without sufficient asparagine, CD8+ T cells were less effective at suppressing tumor growth.
A Nutrient Switch for Cancer-Killing Cells
The study showed that higher asparagine levels in the tumor microenvironment—when bo‑ansB was removed—drove CD8+ T cells to express more of a protein transporter (SLC1A5) on their cell surface, which was important in fighting cancer cells. Stem-like CD8⁺ T cells serve as a renewable source of immune cells that can mature into cancer-killing T cells. Once activated, these killer cells attack tumors by producing strong immune factors that help destroy cancer cells. Blocking SLC1A5 erased the gains from the higher asparagine levels.
Beyond asparagine, the Guo lab is interested in exploring other pathways that may impact tumor burden by suppressing growth or boosting antitumor activity. "Many studies suggest that enzymes produced by our microbiota, as well as the metabolites like small molecules and proteins, could be potential biomarkers for cancer progression," said Dr. Guo, who is also a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease.
This raises the possibility that future cancer care could pair immunotherapy with tailored diets and microbiome-targeted strategies, such as the design of probiotics, engineered native gut bacteria or personalized dietary plans that fine-tune amino acid availability.
"We think it's critical to continue studying interactions between diet, the microbiota and the immune system because different diets may enhance the immune system of one individual but not another, depending on the type of microbiota they have," Dr. Collins said. "Our goal is personalized therapy, where we can tailor a specific diet that will synergize with the microbiota of an individual to boost the immune system against cancer."
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. David Artis .
This research was supported by the National Institutes of Health grants 1DP2HD101401-01, DK135816-01, R01CA299862, R01AI178683, R00AI173660DK126871, AI151599, AI095466, AI095608, AI142213; additional support was provided NIH grants AI172027, DK132244, K99CA290052, R01 CA274534, R01 CA271619 and R01 CA282072. Kenneth Rainin Foundation and the Crohn's & Colitis Foundation also provided funding.
