Enhanced acetate uptake and metabolism in endothelial cells promote tumour angiogenesis and immunosuppression by...

Acetate is the metabolic precursor of acetyl-coenzyme A (CoA), fuelling histone acetylation.

We aimed to investigate whether the acetate-acetylation axis is hijacked in tumour endothelial cells (TECs) to govern hepatocellular carcinoma (HCC) progression.

The endothelial acetate-acetylation axis and its impact on malignant phenotypes and anticancer therapy were systematically dissected using clinical specimens, primary endothelial cells (ECs) from HCC (tumour endothelial cells, TECs) or non-tumour liver tissues (non-tumour endothelial cells, NECs), EC lines and diverse mouse models.

Compared with NECs, TECs showed elevation of acetate transporter (monocarboxylate transporter 1, MCT1), metabolic enzyme ACSS2 and H3K27ac. Acetate was highly enriched within tumour and surrounding parenchyma, and correlated positively with tumour angiogenesis. Functionally, acetate or hepatoma-conditioned media increased endothelial H3K27ac and EC migration, which were attenuated by inhibiting MCT1 or ACSS2. Notably, acetate-treated ECs, but not acetate alone, drived CD8⁺ T cell exhaustion and regulatory T cell (Treg) expansion. In mouse hepatoma allograft models, acetate administration increased H3K27ac levels in TECs, driving angiogenesis, tumour growth and metastasis, while reducing CD8⁺ T cells and expanding Tregs. Mechanistically, acetate orchestrated pro-angiogenic and immunosuppressive transcriptional programmes in ECs via histone acetylation. Therapeutically, pharmacological ACSS2 inhibition, EC-targeting simACSS2-liposomes and adeno-associated virus (AAV)-TIE2-shmACSS2 all decreased H3K27ac levels in TECs, inhibited angiogenesis, increased CD8⁺ T cells and reduced Tregs. Crucially, ACSS2 inhibition synergised with anti-programmed cell death protein 1 (PD-1) to alleviate immunosuppression, curb angiogenesis and suppress tumour progression.

Hepatic acetate accumulation and concomitant MCT1/ACSS2 upregulation in TECs drives endothelial epigenetic remodelling, thus fuelling angiogenesis, immunosuppression and HCC progression. Targeting this metabolic-epigenetic axis represents a novel approach to potentiate HCC therapy and sensitise immunotherapy.