🧫 Mastering the Microbiome
[7/14/25] The gut microbiome impacts cancer treatment success
Featured Article
Microbiota-derived urocanic acid triggered by tyrosine kinase inhibitors potentiates cancer immunotherapy efficacy [Zhang et al., 2025]
🎯 Research Goal
While the cancer death rate has dropped 33% since 1991, there is still great need for better cancer treatments. In the US alone millions of people are diagnosed with cancer each year, and hundreds of thousands will die of the disease. For many cancer drugs, the spectrum of treatment success is wide - some patients respond very well, others poorly. Researchers are still trying to figure out why. Coming up with answers to this question will point the way to improved drug treatments that save many lives.
📑 Past Work
Immune checkpoint blockade (ICB) therapies kill cancer by encouraging the immune system to target tumor cells. ICB drugs like Nivolumab (Opdivo) and Pembrolizumab (Keytruda), used to treat a variety of cancers, block a protein called PD-1 in T cells. This is helpful because cancer cells themselves bind to the PD-1 protein, encouraging T cells to limit their immune activity and leave the tumor alone. If ICB is successful, the brakes are removed and T cells are converted to a cancer-killing state. Though effective for some patients, many are not responsive (in fact, only 10-30% of patients with solid tumors - such as breast, lung, and brain cancer - actually respond to the therapy). More recently it has been shown that combining ICB with another kind of cancer drug called a tyrosine kinase inhibitor (TKI) improves treatment success rates for certain kinds of cancer. Researchers are now exploring why - so that clinicians can better predict which patients will respond well and additional treatment options can be designed that further improve ICB success.
🔑 Key Findings
In this study the researchers investigated how the use of tyrosine kinase inhibitors (TKI) impacted the microbiome - and whether the altered activity of the microbiome during TKI treatment could help explain the improved response to ICB. Prior research has shown that the microbiome influences cancer progression and treatment success. Just as ICB primes immune cells to kill cancer, chemical products produced by bacterial species in the gut microbiome can also influence immune cells, either driving them towards a pro or anti-cancer state.
The researchers first collected fecal samples from cancer patients on TKIs, and extracted metabolites (the chemical products produced by the microbiome).
They then took these metabolites and administered them to mice with colon cancer, showing that the metabolites limited cancer growth.
This anti-tumor effect was accompanied by an increase in active T cells and reduced numbers of another kind of immune cell called a myeloid-derived suppressor cell (MDSCs). Unlike the active T cells these MDSC cells are bad news - as they work to suppress the anti-tumor immune response.
To figure out what microbial metabolites are responsible for this effect, the researchers compared the metabolite profile of TKI-treated to non-treated mice, and found a metabolite called urocanic acid (UCA) at significantly higher levels in the treated group.
They confirmed its relevance by treating mice with UCA alone and showing that it has the same effect of reducing tumor growth, increasing the activation of T cells, and reducing the amount of MDSCs.
What bacteria produce this metabolite? The researchers sequenced the microbiomes of TKI-treated and non-treated mice and found that a certain species of bacteria (M. gordoncarteri) was elevated in the treated group and likely responsible for UCA production.
Again the researchers performed an expeirment to verify - giving mice a dose of M. gordoncarteri and showing that UCA levels rise, tumor growth drops, more T cells are activated, and the MDSC population is depleted.
The researchers came up with a mechanistic explanation for why UCA was having these positive effects. They show that UCA deactivates the NF-κB pathway (by binding to a protein called IκB⍺) in tumor cells. The NF-κB pathway is a cellular program that enables tumor cells to communicate with MDSCs and recruit them to the tumor site. Inhibiting this pathway, then, reduces MDSC counts at the tumor site.
Finally, the researchers showed that M. gordoncarteri UCA production not only influences ICB success in mice, but also likely does in humans as well. For human patients on anti-PD-1 ICB therapy, UCA and M. gordoncarteri levels were elevated in patients who responded well to the drug. Furthermore, patients with higher levels of the bacterium and its metabolite survived longer.
🩺 Clinical Potential
Now that researchers understand some of the underlying factors that promote the success of TKI-ICB combo therapy1, clinicians can use this information to predict how individual patients will respond to the combination of ICB and TKI. Measuring UCA levels in blood and/or fecal samples could help inform clinicians about whether a patient is likely to respond to TKI, or if alternative therapies might be necessary. Their findings also open the door to new treatment strategies. For example, it may be possible to administer M. gordoncarteri or some other UCA-producing probiotic species in humans, priming the microbiome to promote anti-tumor immune cell activity in ICB+TKI treated patients.
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It is likely that TKI improves ICB treatment success by other mechanisms too (for example, by directly affecting cancer cells or immune cells in addition to changing the state of the microbiome) - but UCA production by the gut microbiome does appear to play an important role in improving ICB success.