Scientists at the Salk Institute have found that certain bile acids in the liver suppress immune cells, reducing the effectiveness of immunotherapy for liver cancer. Supplementing with ursodeoxycholic acid (UDCA) reversed this effect in mice, shrinking tumors. UDCA, already approved for other liver conditions, could soon enter clinical trials for cancer treatment.
Immunotherapy has revolutionized treatments for cancers like those of the lung, kidney, and bladder, but it has shown limited success against liver cancer, where cases have nearly tripled over the past four decades. Researchers at the Salk Institute investigated this discrepancy using mouse models and human tumor samples, uncovering that bile acids—molecules the liver produces to aid digestion—interfere with T cells, the immune cells crucial for fighting tumors.
The team identified specific bile acids linked to weakened T cell function and accelerated tumor growth. For instance, elevated levels of conjugated bile acids were found in human liver cancer biopsies. By genetically removing the protein BAAT, which produces these acids, tumor loads in mice decreased significantly. Among 20 tested bile acids, primary ones like TCDCA induced oxidative stress, while secondary ones varied: LCA caused endoplasmic reticulum stress and damaged T cells, but UDCA enhanced T cell activity and attracted more immune cells to the liver.
Supplementing mice with UDCA shrank liver tumors and improved immunotherapy outcomes. "How do organ-specific properties and processes influence the immune response?" asked senior author Susan Kaech, director of Salk's NOMIS Center for Immunobiology and Microbial Pathogenesis. "By investigating these liver-specific features, we have identified several potential ways to regulate bile acids, improve T cell performance, and enhance patient outcomes."
The liver produces over 100 bile acids, and past studies linked high levels to cancer progression without distinguishing individual effects. Lowering BAAT activity and boosting UDCA could strengthen immune responses. "We're already a huge step ahead when it comes to translating our findings to the clinic, because UDCA supplementation is already used to treat liver disease," Kaech noted, adding interest in gut microbiome roles and potential probiotic therapies.
The study, published in Science on October 17, 2025, also suggests benefits for chronic liver disease and obesity by targeting conjugated bile acids. Co-authors include Siva Karthik Varanasi and researchers from UC San Diego, Sanford Burnham Prebys, Columbia University, and others.