Lactate drives immune resistance via a pharmaceutically reversible H3K18la-KIF20A-c-Myc-PD-L1 axis in hepatocellular...

Resistance to immunotherapy, driven by the immunosuppressive tumor microenvironment, remains a major clinical challenge in hepatocellular carcinoma (HCC). Although metabolic reprogramming is a known culprit, the precise epigenetic mechanisms linking lactate accumulation to immune evasion are poorly defined.

Immunohistochemistry analysis of 89 pairs of HCC and paracancerous tissues was conducted to correlate histone h3 lysine 18 lactylation (H3K18la) levels with TNM stage. A separate clinical cohort of 46 patients with HCC was enrolled to assess the association between H3K18la levels and anti-PD-1 therapy resistance. Chromatin immunoprecipitation sequencing in HCC cells, performed to screen for downstream targets, identified kinesin family member 20A (KIF20A). The regulatory relationships among H3K18la, KIF20A, c-Myc, and PD-L1 were verified with dual-luciferase reporter assays and chromatin immunoprecipitation-PCR. The immune evasion mechanism was explored through gene knockdown/overexpression in HCC cells, followed by co-culture with CD8⁺ T cells and functional analysis via flow cytometry. Finally, a subcutaneous mouse xenograft model was established to evaluate the synergistic efficacy of a glycolysis inhibitor combined with anti-PD-1 therapy on tumor growth and the tumor immune microenvironment.

Histone lactylation (forming H3K18la) was identified as a key epigenetic checkpoint linking tumor metabolism to immunotherapy failure in HCC. Elevated H3K18la is a reliable biomarker for tumor progression and resistance to anti-PD-1 therapy. Mechanistically, we discovered that lactate-driven H3K18la directly activates transcription of the oncogene KIF20A. KIF20A in turn stabilizes c-Myc protein, thereby enhancing PD-L1 expression and attenuating anti-tumor immunity. This immunosuppressive phenotype was therapeutically reversible: genetic silencing of KIF20A restored T cell function, and pharmacological inhibition of glycolysis acted synergistically with anti-PD-1 therapy in suppressing tumor growth and extending survival by dismantling the H3K18la-KIF20A axis.

This study deciphered a novel druggable metabolic-epigenetic pathway (lactate-H3K18la-KIF20A-Myc-PD-L1) responsible for immune evasion in HCC. Targeting this axis might offer a promising strategy to reprogram the tumor microenvironment and restore immunotherapy sensitivity.