Cancer ENO2 Induces Histone Lactylation-Mediated M2 Macrophage Polarization and Facilitates Metastasis of Head and Neck Squamous Cell Carcinoma

IF 10.1 1区工程技术 Q1 ENGINEERING, MULTIDISCIPLINARY

Engineering Pub Date : 2025-05-01 DOI:10.1016/j.eng.2024.11.036

Chenran Wang , Lin Tan , Maohua Huang , Yuning Lin , Minxiang Cai , Lijuan Deng , Xinpeng Hu , Shenghui Qiu , Xiaoting Chen , Yiming Zhang , Xiaomei Luo , Changzheng Shi , Minfeng Chen , Wencai Ye , Junqiu Zhang , Dongmei Zhang , Xiangning Liu

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Abstract

Metabolic reprogramming reshapes the tumor microenvironment (TME) and facilitates metastasis, but its molecular mechanisms remain incompletely understood. Here, we identified enolase 2 (ENO2), a critical glycolytic enzyme, as being associated with lymphatic metastasis in head and neck squamous cell carcinoma (HNSCC). Mechanistically, phosphoenolpyruvate (PEP), the metabolite secreted by ENO2-expressing HNSCC cells, drove histone H3 lysine 18 lactylation (H3K18la)-mediated M2 polarization in macrophages, which, in turn, enhanced the epithelial–mesenchymal transition (EMT) and invasiveness of HNSCC cells. Pharmacological inhibition of ENO2 with POMHEX effectively reversed M2 macrophage polarization and inhibited HNSCC lymphatic metastasis. Collectively, our findings underscore the prognostic significance of ENO2 and highlight its potential as a therapeutic target for metastatic HNSCC. Furthermore, we reveal a previously underappreciated role of PEP in modulating the tumor immune microenvironment and tumor metastasis via epigenetic modification.

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肿瘤ENO2诱导组蛋白乳酸化介导的M2巨噬细胞极化并促进头颈部鳞状细胞癌转移

代谢重编程重塑肿瘤微环境（TME）并促进转移，但其分子机制尚不完全清楚。在这里，我们发现烯醇化酶2 (ENO2)，一种关键的糖酵解酶，与头颈部鳞状细胞癌（HNSCC）的淋巴转移有关。在机制上，表达eno2的HNSCC细胞分泌的代谢物磷酸烯醇丙酮酸（PEP）驱动组蛋白H3赖氨酸18乳酸化（H3K18la）介导的巨噬细胞M2极化，从而增强HNSCC细胞的上皮-间质转化（EMT）和侵袭性。POMHEX对ENO2的药理抑制能有效逆转M2巨噬细胞极化，抑制HNSCC淋巴转移。总之，我们的研究结果强调了ENO2的预后意义，并强调了其作为转移性HNSCC治疗靶点的潜力。此外，我们揭示了PEP在通过表观遗传修饰调节肿瘤免疫微环境和肿瘤转移中的作用。

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来源期刊

Engineering Environmental Science-Environmental Engineering

自引率

1.60%

发文量

335

审稿时长

35 days

期刊介绍： Engineering, an international open-access journal initiated by the Chinese Academy of Engineering (CAE) in 2015, serves as a distinguished platform for disseminating cutting-edge advancements in engineering R&D, sharing major research outputs, and highlighting key achievements worldwide. The journal's objectives encompass reporting progress in engineering science, fostering discussions on hot topics, addressing areas of interest, challenges, and prospects in engineering development, while considering human and environmental well-being and ethics in engineering. It aims to inspire breakthroughs and innovations with profound economic and social significance, propelling them to advanced international standards and transforming them into a new productive force. Ultimately, this endeavor seeks to bring about positive changes globally, benefit humanity, and shape a new future.