Evidence has been rising over the past few years that the gut microbiome can significantly influence how well cancer treatments work, especially immunotherapies. But the underlying mechanism has remained unclear. Now, a new study reveals how bacteria in the gut can help determine whether the amino acid asparagine (obtained from diet) will increase tumor growth or activate immune cells against the cancer.
The findings, published in Cell Microbe and Host in the paper, “Microbiota utilization of intestinal amino acids modulates cancer progression and anticancer immunity,” 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 Chunjun Guo, PhD, associate professor of immunology at Weill Cornell.
The researchers first established that some bacteria could deplete amino acids and affect tumor progression in mouse models with human gut microbiota. 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 asparagine to be active.
The team worked with Bacteroides ovatus, a common gut bacterium. When the bo‑ansB gene—which encodes an enzyme that breaks down asparagine—was present, B. ovatus consumes more asparagine in the gut, so less of it is absorbed into the bloodstream and delivered to tumors. When bo‑ansB was knocked out, the bacteria were not able to deplete asparagine in the intestine, so more of the amino acid reached the blood circulation and tumor, demonstrating 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.
The study showed that higher asparagine levels in the tumor microenvironment—when bo‑ansB was removed—drove CD8+ T cells to express more of the 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.
The team 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 Guo.
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,” said Nicholas Collins, PhD, assistant professor of immunology at Weill Cornell. “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.”
