WANG Chenghong, TIAN Manlin
Current Immunology. 2026, 46(4): 506-514.
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To investigate the effect of inhibiting histone H3K18 lactylation (H3K18la) on lung cancer, H3K18la levels were measured in 56 pairs of lung cancer tissues and adjacent normal tissues using immunohistochemistry (IHC). The glycolysis inhibitor 2-deoxy-D-glucose (2-DG) was used to reduce H3K18la level. Mouse Lewis lung carcinoma (LLC) cells were divided into the control group, the 5 mmol/L 2-DG group, the 10 mmol/L 2-DG group, and the 10 mmol/L 2-DG+pcDNA3.1- hypoxia-inducible factor-1α (HIF-1α) group. Cell proliferation was assessed by 5-ethynyl-2＇-deoxyuridine (EdU) assay, and clonogenic ability was determined by colony formation assay. Transcriptome sequencing analyzed differentially expressed genes between the control and the 10 mmol/L 2-DG groups, followed by Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) confirmed the binding of H3K18la to HIF-1α promoter. A subcutaneous xenograft model was established in C57BL/6 mice by inoculating LLC cells were divided into the model group, the 100 mg/kg 2-DG group, the 200 mg/kg 2-DG group, and the 200 mg/kg 2-DG+pcDNA3.1-HIF-1α group. CD8+ T cell infiltration rate in tumor tissue was assessed by immunofluorescence staining. Protein expressions of H3K18la, HIF-1α, and PD-L1 were measured by Western blotting. Levels of granzyme B, TNF-α, and perforin in tumor tissues were quantified by ELISA. The results showed that H3K18la levels were significantly higher in lung cancer tissue compared to that of adjacent tissue. Compared to the control group, both the 5 mmol/L and the 10 mmol/L 2-DG groups showed significantly reduced LLC cell proliferation, colony formation, H3K18la, HIF-1α, PD-L1, and H3K18la binding to HIF-1α promoter. Compared to the 10 mmol/L 2-DG group, the 10 mmol/L 2-DG+pcDNA3.1-HIF-1α group exhibited restored cell proliferation and colony formation ability, along with increased expressions of HIF-1α and PD-L1 (P< 0.01). Compared to the model group, both the 100 mg/kg and the 200 mg/kg 2-DG groups displayed reduced tumor volume, increased CD8+ T cell infiltration rate, elevated concentrations of granzyme B, TNF-α, and perforin, and decreased levels of H3K18la, HIF-1α, and PD-L1. Compared to the 200 mg/kg 2-DG group, the 200 mg/kg 2-DG + pcDNA3.1-HIF-1α group showed increased tumor volume, decreased CD8+ T cell infiltration, reduced concentrations of cytotoxic factors, and upregulated levels of HIF-1α and PD-L1 (P<0.01). Targeting H3K18la level inhibits lung cancer cell growth and enhances T cell infiltration in tumor tissue. This effect is likely mediated through suppression of the HIF-1α/PD-L1 signaling pathway.
