This popular liver supplement can enhance the success of cancer treatment

To explore why liver cancer responds so poorly to immunotherapy, scientists at the Salk Institute examined how the immune system interacts with the liver. Using mouse models and human tumor samples, they discovered that some bile acids — molecules produced by the liver to aid in digestion — can interfere with cancer-fighting immune cells known as T cells.

The team identified several bile acids associated with impaired T-cell function and faster tumor growth. By blocking the production of these acids, they were able to slow or stop tumor development. One bile acid, called ursodeoxycholic acid (UDCA), had the opposite effect, enhancing T-cell activity in the liver. When the researchers increased UDCA levels through supplements, the mice’s liver tumors shrank. Because UDCA supplements are already approved for other liver diseases, scientists believe they could make immunotherapy more effective for liver cancer patients.

The study published in sciencesIt highlights why immune cells behave differently depending on the location of the tumor and identifies new molecular targets to advance liver cancer treatments.

“How do organ-specific characteristics and processes affect the immune response?” asks Professor Susan Kish, lead author of the study and director of Salk’s NOMIS Center for Microbial Immunobiology and Pathogenesis. “The liver has a particularly unique environment, but we didn’t really understand how it affects immune and cancer cells. By studying these liver-specific features, we identified several potential ways to regulate bile acids, improve T-cell performance, and enhance patient outcomes.”

The liver produces more than 100 types of bile acids, which travel through the intestines to help digest fats. To fight liver cancer, T cells must work effectively in this chemical-rich environment. Previous studies have linked high bile acid levels to poor health and the development of cancer, but researchers had not previously distinguished between the effects of individual bile acids.

“Given how T cells perform differently across different organs, tissues and tumors, it puts us in a better position to look for ways to improve cancer treatment,” says Siva Karthik Varanasi, a former postdoctoral researcher in Kaish’s lab and current assistant professor at UMass Chan School of Medicine. “By taking this unique approach, we are able to see that bile acids in the liver significantly impact the ability of T cells to do their job and therefore may be a useful therapeutic target.”

To better understand these effects, the Salk team first analyzed human liver cancer biopsies to determine which bile acids were present. They found elevated levels of conjugated bile acids and tested whether these compounds contributed to tumor growth. When they removed a protein called BAAT, which produces conjugated bile acids, the mice’s tumor loads decreased significantly. This suggests that modulating BAAT activity in humans could improve their response to immunotherapy.

The researchers then examined 20 different bile acids to determine how each affected T cells. Most primary bile acids showed little effect, with the exception of one called TCDCA, which led to oxidative stress – a harmful molecular imbalance. Secondary bile acids had much stronger effects. One, called LCA, damaged T-cell function by causing endoplasmic reticulum stress, while the other, UDCA, boosted T-cell performance and attracted more immune cells to the liver. Increasing UDCA levels through supplementation effectively reduced tumor growth in mice, suggesting a promising strategy for enhancing immunotherapy in HCC.

Together, these results suggest that lowering BAAT and increasing UDCA could help control liver tumor growth and enhance the immune system’s response to treatment.

“We’ve already taken a big step forward when it comes to translating our findings into the clinic, because UDCA supplements are already used to treat liver disease and could easily be tested in liver cancer next,” says Kaish, who also serves as head of NOMIS at Salk. “We’re really excited to explore the role of the gut microbiome in all of this, since bile acids are a big part of that picture — how can we manipulate the ‘good’ and ‘bad’ bacteria in the microbiome to up-regulate bile acid levels? How does the microbiome change during liver cancer? Could probiotics be a therapeutic approach?”

In addition to exploring dietary and microbiome manipulation that could help treat liver cancer, the team is curious to see whether other conditions could be treated by targeting BAAT. Indeed, they believe that chronic liver disease and obesity may benefit from the same reduction in conjugated bile acids.

Katherine John, Katherine Land, Filipina Chung, Satchidananda Panda, April Williams, and Gerald Shadel of SALIC; Jin Li, Liu, Kayla Miller, and General Sing Feng of Diego; Soripta Mark Teneschi, Aaron Havas, Peter Potds of the Sanford Burnham Institute for Medical Discovery; Isaac Jensen and Donna Farmey; Andrea Shetter of Memorial Sheeter. Mark Sundrud Dart.

The work was supported by the National Institutes of Health (NCI CCSG: P30 014195, S10-OD023689, P30 AG068635, P30 CA014195, P01 AG073084, R01 CA240909-04, R21 AI151562, F31CA278581, CCSG Grant P30CA23100, R01DK137061, R01DK133930, DK120515, R01AI143821, R01AI164772, U01AI163063), White Foundation, Helmsley Charitable Trust, Chapman Foundation, Cancer Research Institute, National Cancer Center, NOMIS Foundation, Fellowship Salkexcellerators, Damon Runyon Fellow Audrey Geisel holds chair in the Department of Biomedical Sciences, Altman Institute for Clinical Translational Research (KL2TR001444), San Diego Digestive Disease Research Center, and Dartmouth Cancer Center.