Mechanisms and Clinical Significance of Bile Acid Metabolism Reprogramming in Hepatocellular Carcinoma Immunotherapy Response

Background Hepatocellular carcinoma (HCC) constitutes the foremost cause of cancer-related mortality globally, and patients exhibit significant variations in their response to immunotherapy. Recent research has shown that elevated bile acids (BAs) are closely associated with HCC. Methods We collected surgical tumor samples from six HCC patients and categorized them into recurrence (FA, n = 3) and disease-free survival (WA,n = 3) groups based on one-year postoperative follow-up. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we quantified 36 BAs in tumor tissues. Additionally, we analyzed bile acid synthetase gene expression using The Cancer Genome Atlas (TCGA) data, and explored the regulatory role of chenodeoxycholic acid (CDCA) on macrophage polarization. Results The findings revealed that tumors from patients with favorable treatment response and long-term disease-free survival contained higher levels of primary BAs, whereas recurrent patients showed elevated secondary BAs. Additionally, we found that patients with higher expression of the bile acid synthase gene CYP27A1 had significantly prolonged survival, and this gene could serve as an independent predictor for treatment outcomes. Correlation analysis revealed that high expression of bile acid synthase is associated with weakened. Experiments demonstrated that BAs can influence the functional state of macrophages. Conclusion These findings indicate that the metabolic of BAs is closely linked to the immunotherapy response in HCC. It provides novel targets for metabolic-based therapeutic strategies, with CYP27A1 serving as a potential predictive biomarker.