Immunotherapy has revolutionized cancer treatment in recent years, offering patients the potential for more personalized and effective therapies. By harnessing the power of the immune system, immunotherapy helps the body’s natural defenses fight cancer more effectively. It has proven to be an impactful approach for several types of cancer, including those affecting the lung, kidney, and bladder. However, when it comes to liver cancer, the results have been less impressive, sparking concerns as liver cancer rates have nearly tripled globally in the past four decades.
A growing body of research has sought to understand why immunotherapy tends to be less effective in liver cancer. Scientists have found intriguing answers by exploring the complex interactions between the liver’s environment and the immune system. One significant finding comes from the Salk Institute, where a team of researchers recently uncovered how bile acids in the liver could hinder the body’s immune response against liver tumors.
The Role of Bile Acids in Liver Cancer
Bile acids, which are produced by the liver, play a critical role in digestion and the metabolism of fats in the intestines. The liver produces over 100 different types of bile acids, some of which are conjugated—chemically modified—during their circulation. While bile acids are essential for maintaining digestive health, they may have a much more significant impact than previously recognized in the context of liver disease and cancer. Bile acids are known to contribute to certain disease states, including cancer, and have been shown to negatively affect immune system function, especially in the liver.
Recent studies at the Salk Institute have focused on identifying how bile acids directly influence the function of immune cells, known as T cells, which are key players in the body’s fight against cancer. The liver’s unique cellular environment may impact how T cells are activated and how well they perform their immune functions within the liver. Through these studies, researchers were able to identify specific bile acids that impair T cell activity, contributing to the growth and survival of liver tumors.
Dr. Susan Kaech, the senior author of the study and Director of Salk’s NOMIS Center for Immunobiology and Microbial Pathogenesis, explained that liver-specific features were previously underexplored. “How do organ-specific properties and processes influence the immune response?” Kaech asked, leading to the discovery of critical factors influencing T cell behavior in the liver’s distinct environment. The research suggests that certain bile acids directly inhibit T cell performance, promoting tumor growth in liver cancer patients.
Key Discoveries About Bile Acids and Tumor Growth
The Salk researchers’ investigation involved several stages. First, they cataloged the bile acids present in human liver cancer biopsies. The results revealed that the liver tumor samples contained elevated levels of conjugated bile acids compared to healthy tissues. This observation led the researchers to ask whether these conjugated bile acids were playing a direct role in cancer progression.
To test this hypothesis, the team focused on a specific enzyme, BAAT (bile acid-CoA:amino acid N-acyltransferase), which produces conjugated bile acids. When they removed BAAT from the experimental mice, the researchers observed a notable reduction in tumor burden, pointing to the idea that regulating the levels of conjugated bile acids—specifically by controlling BAAT production—could improve the efficacy of immunotherapies for liver cancer.
Impact on T Cell Function
After addressing the role of bile acid production in liver cancer progression, the researchers delved deeper into how different bile acids directly affected the function of immune cells. They isolated 20 different bile acids and examined their impact on T cells. Interestingly, the bile acids were shown to have different effects based on their chemical composition and the pathways they triggered in the immune system.
Some primary bile acids had minimal impact, while others, like TCDCA (taurocholic acid), induced oxidative stress in T cells. Oxidative stress damages the integrity of cells and tissues, preventing the T cells from performing their cancer-fighting functions. More impactful, however, were secondary bile acids, especially two: LCA (lithocholic acid) and UDCA (ursodeoxycholic acid).
LCA was found to cause endoplasmic reticulum (ER) stress within T cells. This stress hindered the ability of the T cells to fold and modify proteins correctly, impairing their immune response. On the other hand, UDCA, an otherwise common bile acid used to treat liver diseases such as primary biliary cholangitis, had a positive impact on T cell function. UDCA enhanced the recruitment of immune cells to liver tumors and promoted healthier T cell activity.
Through dietary supplementation of UDCA, the team was able to control tumor growth in mice suffering from liver cancer. Since UDCA is already used to treat other liver diseases, this could present an easy and promising way to improve the outcomes of immunotherapy for liver cancer patients.
Implications for Immunotherapy and Future Treatments
The findings from the Salk Institute hold significant potential for enhancing immunotherapy for liver cancer. Professor Kaech, also the NOMIS Chair at Salk, is excited about the clinical implications of this work, especially since UDCA supplementation is already in use for other liver diseases. Because of this, UDCA could easily be integrated into liver cancer treatment strategies, potentially making existing immunotherapies more effective.
“By investigating liver-specific bile acids, we are not only revealing new ways to boost the performance of T cells, but we are also identifying molecular targets that could help revolutionize liver cancer treatment,” Dr. Kaech stated.
These new insights challenge the standard approach to liver cancer treatment by considering the liver’s complex biological environment in a new light. For a long time, scientists have tried to improve cancer treatments by focusing only on the tumor itself, often overlooking the host’s surrounding environment and immune function. The Salk researchers have shown that organ-specific features like bile acid profiles in the liver matter considerably in influencing how immune cells function, opening up fresh perspectives in cancer immunotherapy.
Exploring the Gut Microbiome and Future Research
In addition to dietary changes such as UDCA supplementation, the Salk researchers also highlighted the potential role of the gut microbiome in regulating bile acid levels. Since bile acids are closely linked with gut bacteria, researchers are beginning to explore how manipulating the microbiome could influence cancer treatments. Certain bacteria are thought to modify bile acid metabolism, possibly affecting cancer progression and the immune response. For example, “good” bacteria in the gut might reduce harmful bile acid levels, thereby improving the immune response in liver cancer.
Additionally, the research team is considering the potential use of probiotics as a therapeutic strategy. Could introducing specific probiotic strains into a patient’s gut microbiome improve liver cancer treatment outcomes by regulating bile acid levels? Future studies into the microbiome’s influence on liver cancer may lead to new combination treatments, integrating probiotic-based therapies with existing immunotherapy approaches.
Broader Applications Beyond Liver Cancer
While much of this research focuses on liver cancer, the implications extend beyond just one organ system. The discovery that regulating bile acids can influence T cell function opens new opportunities for addressing other conditions and diseases, especially chronic liver conditions like cirrhosis or obesity. The findings suggest that targeting BAAT to reduce conjugated bile acid levels could benefit patients with chronic liver diseases, in addition to those with liver cancer.
As the team continues their exploration of the relationship between bile acids, the immune system, and liver cancer, they aim to test their findings in human clinical trials. The hope is that manipulating bile acid levels will significantly improve the efficacy of immunotherapy, offering a new line of treatment for liver cancer and beyond.
Conclusion
The work from the Salk Institute has revealed an exciting new frontier in liver cancer treatment, highlighting how liver-specific bile acids influence immune response. By targeting key bile acids like UDCA to boost T cell activity and suppress tumor growth, the researchers have opened a new window for enhancing immunotherapy. With further exploration into the gut microbiome and the broader clinical applications of bile acid regulation, there is a lot of optimism that these findings will transform the way liver cancer and other chronic liver conditions are treated in the future.
Reference: Siva Karthik Varanasi et al, Bile acid synthesis impedes tumor-specific T cell responses during liver cancer, Science (2025). DOI: 10.1126/science.adl4100
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