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

Model of tumor cell-derived ENO2 promoting macrophage M2 polarization and facilitating metastasis in HNSCC. Schematic representation depicts the mechanism by which the ENO2-derived oncometabolite PEP directly binds to HDAC1 and thereby promotes H3K18la, which promotes macrophage polarization and leads to metastasis in HNSCC (created with BioRender.com). 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.