Xu Shaowan, Peng Xin, Wang Zhenfang, Le Chenchen, Wu Xiangkun, Zeng Zhicheng, Zeng Sisi, Zhang Ceng, Qiu Mingxing, Zou Xin, Zhang Hongxia, Wang Feifei, Kang Wei, Ding Yanqing, Liang Li
Department of Pathology, Nanfang Hospital and School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
Int J Biol Sci. 2025 Jun 23;21(10):4388-4409. doi: 10.7150/ijbs.110750. eCollection 2025.
Abnormal metabolism processes play a crucial role in the establishment of the pre-metastatic niche (PMN) and the subsequent metastasis to distant organs. However, the precise mechanisms underlying the lipid metabolic reprogramming of macrophages within the liver PMN remain elusive. In this study, we observed an upregulation of fatty acid-binding protein 7 (FABP7) in liver macrophages, which resulted in the accumulation of lipid droplets (LDs) within the PMN of colorectal cancer and pancreatic ductal adenocarcinoma. This accumulation was found to be mediated by the HIF-1α-induced expression of FABP7, which in turn enhanced DGAT1 activity in these macrophages. Furthermore, FABP7-induced lipid-laden macrophages were observed to deliver lipids to CD8 T and tumor cells via exosomes. This process led to CD8 T cell dysfunction and increased tumor cell proliferation through metabolic reprogramming. Importantly, genetic knockout or pharmacological inhibition of FABP7 reduced liver metastasis. Our findings reveal a novel mechanism involving FABP7-mediated LD in macrophages that contributes to liver PMN formation and metastasis. This suggests that targeting FABP7 may offer prognostic and therapeutic potential in addressing liver metastasis.
异常代谢过程在转移前生态位（PMN）的建立以及随后向远处器官的转移中起着关键作用。然而，肝脏PMN内巨噬细胞脂质代谢重编程的精确机制仍不清楚。在本研究中，我们观察到肝脏巨噬细胞中脂肪酸结合蛋白7（FABP7）上调，这导致结直肠癌和胰腺导管腺癌PMN内脂滴（LDs）积累。发现这种积累是由HIF-1α诱导的FABP7表达介导的，这反过来又增强了这些巨噬细胞中的二酰甘油酰基转移酶1（DGAT1）活性。此外，观察到FABP7诱导的富含脂质的巨噬细胞通过外泌体将脂质传递给CD8 T细胞和肿瘤细胞。这一过程通过代谢重编程导致CD8 T细胞功能障碍并增加肿瘤细胞增殖。重要的是，FABP7的基因敲除或药理学抑制减少了肝转移。我们的研究结果揭示了一种涉及巨噬细胞中FABP7介导的LD的新机制，该机制有助于肝脏PMN的形成和转移。这表明靶向FABP7可能在解决肝转移方面具有预后和治疗潜力。
