FABP5+ lipid-loaded macrophages process tumour-derived unsaturated fatty acid signal to suppress T-cell antitumour immunity

作者：Xuguang Yang, Bo Deng, Weiwei Zhao, Yangyang Guo, Yaqi Wan, Zhihao Wu, Sheng Su, Jingyan Gu, Xiaoqian Hu, Wenxue Feng, Chencheng Hu, Jia Li, Yanyong Xu, Xiaowu Huang, Yuli Lin · 发表于：Journal of Hepatology · 年份：2024 · DOI：10.1016/j.jhep.2024.09.029 · 被引用次数：96 · 研究领域：Immune cells in cancer、Cancer, Lipids, and Metabolism、Peroxisome Proliferator-Activated Receptors

Background & Aims Tumour-associated macrophages (TAMs) contribute to hepatocellular carcinoma (HCC) progression. However, while the pro-tumour and immunosuppressive roles of lipid-loaded macrophages are well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear. Methods Single-cell RNA sequencing was performed on mouse and human HCC tumour samples to elucidate the landscape of HCC TAMs. Macrophages were stimulated with various long-chain unsaturated fatty acids (UFAs) to assess immunosuppressive molecule expression in vitro . Additionally, in vivo and in vitro studies were conducted using mice with macrophage-specific deficiencies in fatty acid-binding protein 5 (FABP5) or peroxisome proliferator-activated receptor γ (PPARγ). Results Single-cell RNA sequencing identified a subpopulation of FABP5 + lipid-loaded TAMs characterized by enhanced immune checkpoint blocker ligands and immunosuppressive molecules in an oncogene-mutant HCC mouse model and human HCC tumours. Mechanistically, long-chain UFAs released by tumour cells activate PPARγ via FABP5, resulting in immunosuppressive properties in TAMs. FABP5 deficiency in macrophages decreases immunosuppressive molecule expression, enhances T cell-dependent antitumour immunity, diminishes HCC growth, and improves immunotherapy efficacy. Conclusions This study demonstrates that UFAs promote tumourigenesis by enhancing the immunosuppressive tumour microenvironment via FABP...