肿瘤相关巨噬细胞 (TAM) 有助于肝细胞癌 (HCC) 的进展。然而，虽然脂质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 肿瘤样本进行了单细胞 RNA 测序阐明 HCC TAM 的概况。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，还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 (PPAR) 巨噬细胞特异性缺陷的小鼠进行了体内和体外研究。单细胞 RNA 测序鉴定了 FABP5 脂质负载的亚群TAM 的特点是在癌基因突变 HCC 小鼠模型和人类 HCC 肿瘤中增强免疫检查点阻断剂配体和免疫抑制分子。从机制上讲，肿瘤细胞释放的长链 UFA 通过 FABP5 激活 PPAR，从而产生 TAM 免疫抑制特性。巨噬细针对这一途径改善肿瘤免疫治疗的概念。版权所有 © 2024 欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。

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 in 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 molecules 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 (PPAR).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 PPARvia FABP5, resulting in TAM immunosuppressive properties. FABP5 deficiency in macrophages decreases immunosuppressive molecules expression, enhances T-cell-dependent antitumor immunity, diminishes HCC growth, and improves immunotherapy efficacy.This study demonstrates that UFAs promote tumourigenesis by enhancing the immunosuppressive tumour microenvironment via FABP5-PPAR signaling and provides a proof-of-concept for targeting this pathway to improve tumour immunotherapy.Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.