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.

中文翻译：

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己糖激酶 2 感应肿瘤相关巨噬细胞中的果糖以促进结直肠癌生长


果糖通过酮糖激酶介导的结直肠上皮代谢与结直肠癌肿瘤发生和转移有关，但其在肿瘤免疫微环境中的作用在很大程度上仍然未知。在这里，我们表明适量的果糖在不影响肥胖和相关并发症的情况下，通过抑制 M1 样巨噬细胞的极化来促进结直肠癌肿瘤的发生和生长。果糖抑制 M1 样巨噬细胞极化，独立于果糖介导的代谢。相反，它作为信号分子促进己糖激酶 2 和肌醇 1,4,5-三磷酸盐受体 3 型之间的相互作用，肌醇是内质网上主要的 Ca²⁺ 通道。这种相互作用降低了胞质溶胶和线粒体中的 Ca²⁺ 水平，从而抑制了丝裂原活化蛋白激酶 （MAPK） 和信号转导和转录激活因子 1 （STAT1） 的激活以及包含 NOD、LRR 和pyrin 结构域的蛋白 3 （NLRP3） 炎性小体激活。因此，这阻碍了 M1 样巨噬细胞极化。我们的研究强调了果糖作为一种信号分子的关键作用，它损害了 M1 样巨噬细胞对肿瘤生长的极化。