FABP5+ lipid-loaded macrophages process tumour-derived unsaturated fatty acid signal to suppress T-cell antitumour immunity
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
Abstract
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 FABP5-PPARγ signalling and provides a proof-of-concept for targeting this pathway to improve the efficacy of tumour immunotherapy . Impact and implications Despite the role of tumour-associated macrophages (TAMs) in promoting tumour progression being well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear. Our study reveals that FABP5-mediated unsaturated fatty acid metabolism in TAMs is crucial for modulating antitumour T-cell immunity and influencing the efficacy of immunotherapy . This finding provides novel insights into the immunomodulatory roles of FABP5 + lipid-loaded TAMs in hepatocellular carcinoma and suggests that targeting FABP5 could offer a new approach to liver cancer treatment.