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

Jiang Zhu; Xinye Dai; Ting Luo; Qingbo Zhou; Xuping Feng; Chang Liu; Buzhe Zhang; Bangjie Yin; Pu Wu; Ruihan Luo; Fengwei Gao; Jing Jing; Kunlin Xie; Lü Tian; Hong Wu

doi:10.1016/j.celrep.2026.117761

July 28, 2026Cell ReportsOpen Access

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

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Key Points

This study examines how H3K18 lactylation impacts CD8+ T cell exclusion and resistance to anti-PD-1 therapy in hepatocellular carcinoma (HCC).
Analyzed H3K18 lactylation levels in HCC and their correlation with anti-PD-1 response.
Inhibited H3K18 lactylation to observe effects on HCC progression and CD8+ T cell activity.
Utilized a combination of GLUT1 inhibitor, anti-CCL2 antibody, and anti-PD-1 antibody for enhanced antitumor immunity.
High levels of H3K18 lactylation correlated with reduced CD8+ T cell infiltration and poor prognosis.
Inhibition of H3K18 lactylation led to reduced HCC progression and increased CD8+ T cell immune responses.
The triple combination therapy significantly enhanced CD8+ T cell antitumor immunity, suggesting potential for improved treatment outcomes.

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Implication

Investigates H3K18 lactylation's role in CD8+ T cell exclusion in HCC, suggesting new therapeutic strategies.

Abstract

Glycolytic metabolism promotes an immunosuppressive microenvironment in HCC, but its role in immunotherapy resistance is unclear. Patients with HCC with high 18 F-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.

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Zhu et al. (2026) studied this question.

synapsesocial.com/papers/6a6af51160e2b924d3ea0bc8 https://doi.org/10.1016/j.celrep.2026.117761

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

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

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