Yang Xuguang, Deng Bo, Zhao Weiwei, Guo Yangyang, Wan Yaqi, Wu Zhihao, Su Sheng, Gu Jingyan, Hu Xiaoqian, Feng Wenxue, Hu Chencheng, Li Jia, Xu Yanyong, Huang Xiaowu, Lin Yuli
Clinical Research Center, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China; Department of Immunology of Basic Medical Sciences; Shanghai Pudong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.
J Hepatol. 2025 Apr;82(4):676-689. doi: 10.1016/j.jhep.2024.09.029. Epub 2024 Sep 30.
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.
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).
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.
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.
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.
肿瘤相关巨噬细胞（TAM）促进肝细胞癌（HCC）进展。然而，虽然脂质负载巨噬细胞的促肿瘤和免疫抑制作用已得到充分证实，但脂质代谢增强TAM促肿瘤作用的机制仍不清楚。
对小鼠和人类HCC肿瘤样本进行单细胞RNA测序，以阐明HCC中TAM的情况。用各种长链不饱和脂肪酸（UFA）刺激巨噬细胞，以评估体外免疫抑制分子的表达。此外，使用脂肪酸结合蛋白5（FABP5）或过氧化物酶体增殖物激活受体γ（PPARγ）巨噬细胞特异性缺陷的小鼠进行体内和体外研究。
单细胞RNA测序在癌基因突变的HCC小鼠模型和人类HCC肿瘤中鉴定出一个FABP5脂质负载TAM亚群，其特征是免疫检查点阻断配体和免疫抑制分子增加。机制上，肿瘤细胞释放的长链UFA通过FABP5激活PPARγ，导致TAM具有免疫抑制特性。巨噬细胞中FABP5缺陷可降低免疫抑制分子表达，增强T细胞依赖性抗肿瘤免疫，减少HCC生长，并提高免疫治疗效果。
本研究表明，UFA通过FABP5-PPARγ信号增强免疫抑制性肿瘤微环境来促进肿瘤发生，并为靶向该途径提高肿瘤免疫治疗疗效提供了概念验证。
尽管肿瘤相关巨噬细胞（TAM）促进肿瘤进展的作用已得到充分证实，但脂质代谢增强TAM促肿瘤作用的机制仍不清楚。我们的研究表明，TAM中FABP5介导的不饱和脂肪酸代谢对于调节抗肿瘤T细胞免疫和影响免疫治疗疗效至关重要。这一发现为FABP5脂质负载TAM在肝细胞癌中的免疫调节作用提供了新见解，并表明靶向FABP5可能为肝癌治疗提供新方法。
