H3K18 lactylation drives CD8+ T cell exclusion and anti-PD-1 resistance in hepatocellular carcinoma.

Glycolytic metabolism promotes an immunosuppressive microenvironment in HCC, but its role in immunotherapy resistance is unclear. Patients with HCC with high 18F-FDG uptake on PET/CT show reduced anti-PD-1 response. High glycolysis-driven H3K18la levels correlate with immunotherapy resistance, limited CD8+ T cell infiltration, and poor prognosis. Inhibiting H3K18la suppresses HCC progression and enhances CD8+ T cell antitumor immunity. Mechanistically, H3K18la increases chromatin accessibility at TRPS1 and ETV1 promoters, upregulating their transcription. TRPS1 reinforces glycolysis and GLUT1-mediated resistance to CD8+ T cell bystander killing, while ETV1-driven CCL2 creates an immunosuppressive niche limiting CD8+ T cell accumulation. Triple combination of the GLUT1 inhibitor BAY-876, anti-CCL2 antibody, and anti-PD-1 antibody potentiates CD8+ T cell antitumor immunity. The H3K18la-TRPS1/ETV1-GLUT1/CCL2 axis serves as a biomarker for immunotherapy resistance, and disrupting this axis sensitizes HCC to immunotherapy.