中国科学院生物物理研究所卜鹏程等研究人员合作发现，己糖激酶2在肿瘤相关巨噬细胞中感知果糖以促进结直肠癌的生长。该研究于2024年10月28日在线发表于国际一流学术期刊《细胞—代谢》。

研究人员表明适量的果糖在不影响肥胖及其相关并发症的情况下，通过抑制M1样巨噬细胞的极化，促进结直肠癌的肿瘤发生和生长。果糖不依赖于果糖介导的代谢抑制M1样巨噬细胞的极化。相反，它作为信号分子促进己糖激酶2与内质网主要的Ca²⁺通道（肌醇1,4,5-三磷酸受体类型3）之间的相互作用。

该相互作用降低了细胞质和线粒体中的Ca²⁺水平，从而抑制了丝裂原活化蛋白激酶（MAPK）和信号转导与转录激活因子1（STAT1）的激活以及NLRP3（NOD-, LRR- and pyrin domain-containing protein 3）炎性小体的激活。因此，这阻碍了M1样巨噬细胞的极化。

该研究强调了果糖作为信号分子的关键作用，它通过抑制M1样巨噬细胞的极化来促进肿瘤生长。

据了解，果糖与结直肠癌的肿瘤发生和转移有关，这主要是通过在结直肠上皮中的酮己糖激酶介导的代谢实现的，但其在肿瘤免疫微环境中的作用仍然大量未知。

附：英文原文

Title: Hexokinase 2 senses fructose in tumor-associated macrophages to promote colorectal cancer growth

Author: Huiwen Yan, Zhi Wang, Da Teng, Xiaodong Chen, Zijing Zhu, Huan Chen, Wen Wang, Ziyuan Wei, Zhenzhen Wu, Qian Chai, Fei Zhang, Youwang Wang, Kaile Shu, Shaotang Li, Guizhi Shi, Mingzhao Zhu, Hai-long Piao, Xian Shen, Pengcheng Bu

Issue&Volume: 2024-10-28

Abstract: Fructose is associated with colorectal cancer tumorigenesis and metastasis through ketohexokinase-mediated metabolism in the colorectal epithelium, yet its role in the tumor immune microenvironment remains largely unknown. Here, we show that a modest amount of fructose, without affecting obesity and associated complications, promotes colorectal cancer tumorigenesis and growth by suppressing the polarization of M1-like macrophages. Fructose inhibits M1-like macrophage polarization independently of fructose-mediated metabolism. Instead, it serves as a signal molecule to promote the interaction between hexokinase 2 and inositol 1,4,5-trisphophate receptor type 3, the predominant Ca2+ channel on the endoplasmic reticulum. The interaction reduces Ca2+ levels in cytosol and mitochondria, thereby suppressing the activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 1 (STAT1) as well as NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. Consequently, this impedes M1-like macrophage polarization. Our study highlights the critical role of fructose as a signaling molecule that impairs the polarization of M1-like macrophages for tumor growth.

DOI: 10.1016/j.cmet.2024.10.002

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00398-X