Cell Metabolism, 28 October, 2024, DOI：https://doi.org/10.1016/j.cmet.2024.10.002

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

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

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.

Article link：https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00398-X