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Abstract：
Neuroblastoma (NB) is the most common and deadliest extracranial solid tumor in children. Targeting tumor-associated macrophages (TAMs) is a strategy for attenuating tumor-promoting states. The crosstalk between cancer cells and TAMs plays a pivotal role in mediating tumor progression in NB. The overexpression of Hexokinase-3 (HK3), a pivotal enzyme in glucose metabolism, has been associated with poor prognosis in NB patients. Furthermore, it correlates with the infiltration of M2-like macrophages within NB tumors, indicating its significant involvement in tumor progression. Therefore, HK3 not only directly regulates the malignant biological behaviors of tumor cells, such as proliferation, migration, and invasion, but also recruits and polarizes M2-like macrophages through the PI3K/AKT-CXCL14 axis in neuroblastoma. The secretion of lactate and histone lactylation alterations within tumor cells accompanies this interaction. Additionally, elevated expression of HK3 in M2-TAMs was found at the same time. Modulating HK3 within M2-TAMs alters the biological behavior of tumor cells, as demonstrated by our in vitro studies. This study highlights the pivotal role of HK3 in the progression of NB malignancy and its intricate regulatory network with M2-TAMs. It establishes HK3 as a promising dual-functional biomarker and therapeutic target in combating neuroblastoma.
摘要：
神经母细胞瘤（NB）是儿童最常见和最致命的颅外实体瘤。靶向肿瘤相关巨噬细胞(TAM)是用于减弱肿瘤促进状态的策略。癌细胞和TAM之间的串扰在介导NB中的肿瘤进展中起着关键作用。己糖激酶-3(HK3)的过表达,葡萄糖代谢中的关键酶，与NB患者预后不良有关。此外，它与NB肿瘤中M2样巨噬细胞的浸润有关，表明其显著参与肿瘤进展。因此,HK3不仅直接调控肿瘤细胞的恶性生物学行为,如扩散，迁移,和入侵,而且在神经母细胞瘤中通过PI3K/AKT-CXCL14轴募集和极化M2样巨噬细胞。这种相互作用伴随着肿瘤细胞内乳酸和组蛋白的分泌。此外,同时发现M2-TAMs中HK3的表达升高。调节M2-TAM中的HK3改变了肿瘤细胞的生物学行为，正如我们的体外研究所证明的。这项研究强调了HK3在NB恶性肿瘤进展中的关键作用及其与M2-TAM的复杂调节网络。它确立了HK3作为对抗神经母细胞瘤的有前途的双功能生物标志物和治疗靶标。
