Accumulating evidence shows a close association between various types of bile acids (BAs) and hepatocellular carcinoma (HCC), and they have been revealed to affect tumor immune response and progression mainly by regulating Farnesoid X receptor (FXR). Nevertheless, the roles of Norcholic acid(NorCA) in HCC progression remain unknown yet. In this study, herein we demonstrate that NorCA can promote HCC cell proliferation, migration and invasion through negatively regulating FXR. Additionally, NorCA can increase PD-L1 level on the surfaces of HCC cells and their exosomes, and NorCA-induced exosomes dramatically dampen the function of CD4⁺T cells, thereby inducing an immunosuppressive microenvironment. Meanwhile, a negative correlation between PD-L1 and FXR expression in human HCC specimens was identified, and HCC patients with FXR^lowPD-L1^high expression exhibit a rather dismal survival outcome. Importantly, FXR agonist (GW4064) can synergize with anti-PD-1 antibody (Ab) to inhibit HCC growth in tumor-bearing models. Taken together, NorCA can promote HCC progression and immune invasion by inhibiting FXR signaling, implying a superiority of the combination of FXR agonist and anti‐PD‐1 Ab to the monotherapy of immune checkpoint inhibitor in combating HCC. However, more well-designed animal experiments and clinical trials are warranted to further confirm our findings in future due to the limitations in our study.

越来越多的证据表明，各种类型的胆汁酸 (BA) 与肝细胞癌 (HCC) 之间存在密切关联，并且已发现它们主要通过调节法尼醇 X 受体 (FXR) 来影响肿瘤免疫反应和进展。然而，降胆酸（NorCA）在 HCC 进展中的作用仍然未知。在本研究中，我们证明 NorCA 可以通过负调节 FXR 促进 HCC 细胞增殖、迁移和侵袭。此外，NorCA 可以增加 HCC 细胞及其外泌体表面的 PD-L1 水平，并且 NorCA 诱导的外泌体显着抑制 CD4 ⁺T 细胞，从而诱导免疫抑制微环境。同时，确定了人 HCC 标本中 PD-L1 和 FXR 表达之间的负相关，具有 FXR^低PD-L1^高表达的HCC 患者表现出相当惨淡的生存结果。重要的是，FXR 激动剂 (GW4064) 可以与抗 PD-1 抗体 (Ab) 协同抑制荷瘤模型中的 HCC 生长。总之，NorCA 可以通过抑制 FXR 信号传导促进 HCC 进展和免疫侵袭，这意味着 FXR 激动剂和抗 PD-1 Ab 的组合在对抗 HCC 方面优于免疫检查点抑制剂的单一疗法。然而，由于我们研究的局限性，需要更多设计良好的动物实验和临床试验来进一步证实我们的发现。