GCDCA promotes hepatocellular carcinoma progression through S1PR2/PI3K/AKT-mediated polarization of M2-type macrophages

Li Zhang^1,2,3*Mengmeng Xue^1,2,3Wei Yu³Kuizhi Zhang^1,2,3Yu Chen^1,2,3Luyao Zhang³Hengyan Zhang³Simin Lu³Min Tao^1,2,3Haixin Yan⁴Lixin Wei⁵Gang Lv^6*Lu Gao^5*

• ¹Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China
• ²School of Pharmacy, Anhui Medical University, Hefei, China
• ³Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China
• ⁴Department of Urology, The Fourth Affiliated Hospital of Anhui Medical University, Chaohu, China
• ⁵Department of Tumor Immunology and Gene Therapy Center, National Center for Liver Cancer, Naval Medical University, Shanghai, China
• ⁶Department of General Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing, China

Disorders in bile acid metabolism are crucial mechanisms contributing to the occurrence and development of hepatocellular carcinoma (HCC). As a major cause of cancer-related deaths worldwide, HCC progression is intricately related to immune regulation in the tumor microenvironment (TME), especially in tumor-associated macrophages (TAM), which play a key role in regulating the proliferation, invasion, and immune escape of HCC. However, the mechanism by which BA affects HCC progression by influencing the TME and thus the progression of HCC has not been fully elucidated. We investigated the function of glycochenodeoxycholic acid (GCDCA) in HCC progression, focusing on the mechanisms by which it induces M2-type macrophage polarization by activating the S1PR2/PI3K/AKT signaling pathway and drives HCC progression by promoting tumor cell stemness. First, we observed cancer stem cells (CSCs) in the TME using single-cell sequencing and identified a subpopulation of CSCs with high malignancy. In vivo experiments demonstrated that GCDCA promoted liver cancer progression and enhanced the stemness of liver cancer cells through GCDCA intervention in a primary liver cancer model. Further exploration of the mechanism revealed that GCDCA promoted cancer stem cell growth by activating the S1PR2 receptor on macrophages and the S1PR2/PI3K/AKT signaling pathway to induce macrophage polarization toward the M2 type.