癌症相关 ENO2 通过介导组蛋白乳酸化诱导 M2 型巨噬细胞极化促进头颈部鳞状细胞癌的转移

王晨然a,b,c,d, 谭霖a,c,d, 黄茂华a,c,d, 林宇宁a,c,d, 蔡明详b, 邓丽娟a,c,e, 胡欣朋f, 邱胜辉g, 陈晓婷a,c,d, 张益铭a,c,d, 罗小美a,c,d, 史长征f, 陈敏锋a,c,d, 叶文才a,c,d, 张君秋a,c,d,*(), 张冬梅a,c,d,*(), 刘湘宁b,*()

工程（英文） ›› 2025, Vol. 48 ›› Issue (5) : 262-276.

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工程（英文） ›› 2025, Vol. 48 ›› Issue (5) : 262-276. DOI: 10.1016/j.eng.2024.11.036
Article

 癌症相关 ENO2 通过介导组蛋白乳酸化诱导 M2 型巨噬细胞极化促进头颈部鳞状细胞癌的转移

  • 王晨然a,b,c,d, 谭霖a,c,d, 黄茂华a,c,d, 林宇宁a,c,d, 蔡明详b, 邓丽娟a,c,e, 胡欣朋f, 邱胜辉g, 陈晓婷a,c,d, 张益铭a,c,d, 罗小美a,c,d, 史长征f, 陈敏锋a,c,d, 叶文才a,c,d, 张君秋a,c,d,*(), 张冬梅a,c,d,*(), 刘湘宁b,*()
作者信息 +

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

  • Chenran Wanga,b,c,d,#, Lin Tana,c,d,#, Maohua Huanga,c,d,#, Yuning Lina,c,d, Minxiang Caib, Lijuan Denga,c,e, Xinpeng Huf, Shenghui Qiug, Xiaoting Chena,c,d, Yiming Zhanga,c,d, Xiaomei Luoa,c,d, Changzheng Shif, Minfeng Chena,c,d, Wencai Yea,c,d, Junqiu Zhanga,c,d,*(), Dongmei Zhanga,c,d,*(), Xiangning Liub,*()
Author information +
History +

摘要

 肿瘤代谢重编程通过重塑肿瘤微环境（TME）促进转移，但其分子机制仍有待深入解析。本研究旨在探讨烯醇化酶 2（ENO2）在头颈部鳞状细胞癌（HNSCC）淋巴转移中的作用及机制。研究发现 ENO2 高表达与 HNSCC 淋巴结转移显著相关，且其表达水平与患者预后呈负相关。机制研究表明，ENO2 通过增强糖酵解代谢，促使肿瘤细胞分泌磷酸烯醇丙酮酸（PEP）；该代谢产物进入肿瘤相关巨噬细胞（TAMs）后，通过诱导组蛋白 H3 第 18 位赖氨酸乳酸化（H3K18la）修饰，驱动巨噬细胞向免疫抑制性 M2 型极化。极化后的 M2 型巨噬细胞通过旁分泌作用促进 HNSCC 细胞上皮 - 间质转化（EMT）及侵袭能力，形成 “肿瘤细胞 - 巨噬细胞” 互作的促转移微环境。功能验证显示，靶向 ENO2 的药理学抑制剂 POMHEX 可显著逆转巨噬细胞极化表型，抑制体内外淋巴转移进程。本研究不仅证实 ENO2 可作为 HNSCC 预后评估的生物标志物及潜在治疗靶点，更首次阐明糖酵解代谢产物 PEP 通过组蛋白乳酸化修饰调控肿瘤免疫微环境的新机制，为转移性肿瘤的精准治疗提供了新思路。

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 (EMT) transition 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.

关键词

 烯醇化酶 2 （ENO2） / 头颈部鳞状细胞癌 / 肿瘤淋巴结转移 / 磷酸烯醇丙酮酸 / 组蛋白 H3 第 18 位赖氨酸乳酸化（H3K18la） / M2型巨噬细胞

Keywords

ENO2 / HNSCC / Lymph node metastasis / Phosphoenolpyruvate / H3K18la / M2 macrophages

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王晨然, 谭霖, 黄茂华, 林宇宁, 蔡明详, 邓丽娟, 胡欣朋, 邱胜辉, 陈晓婷, 张益铭, 罗小美, 史长征, 陈敏锋, 叶文才, 张君秋, 张冬梅, 刘湘宁.  癌症相关 ENO2 通过介导组蛋白乳酸化诱导 M2 型巨噬细胞极化促进头颈部鳞状细胞癌的转移. Engineering. 2025, 48(5): 262-276 https://doi.org/10.1016/j.eng.2024.11.036

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