Blocking ACLY Enzyme Slashes Liver Cancer Tumors and Reboots Immune Attack

Hepatocellular carcinoma (HCC) driven by metabolic dysfunction-associated steatohepatitis (MASH) is a rapidly growing cancer type that is notoriously resistant to immunotherapy. Its highly immunosuppressive tumor microenvironment limits the effectiveness of checkpoint inhibitors and other standard treatments, creating an urgent need for novel therapeutic strategies that address both tumor cell metabolism and immune evasion simultaneously.

This study focused on ATP citrate lyase (ACLY), a central metabolic enzyme that converts citrate into acetyl-CoA, linking nutrient availability to lipid biosynthesis and epigenetic gene regulation via histone acetylation. The researchers first established a new mouse model of MASH-HCC using diethylnitrosamine (DEN) combined with a Western diet high in fat, fructose, and cholesterol, which closely recapitulates human disease features including steatosis, ballooning, Mallory-Denk bodies, and lymphocyte infiltration. Hepatocyte-specific and tumor-specific genetic deletion of ACLY reduced neoplastic lesions by more than 70%, establishing a strong causal role for this enzyme in MASH-HCC progression.

To translate these findings therapeutically, the team used phenotypic screening to identify EVT0185, a novel orally bioavailable ACLY inhibitor. Cryo-electron microscopy revealed that EVT0185 is first converted to a CoA thioester (EVT0185-CoA) by the hepatic transporter SLC27A2, and this activated form directly occupies the CoA-binding pocket of ACLY with high specificity. In three independent mouse models of MASH-HCC, oral EVT0185 administration dramatically reduced tumor burden as monotherapy. Critically, it also synergized with current standard-of-care treatments including the tyrosine kinase inhibitor sorafenib and anti-PD-1 immunotherapy, offering a combinatorial therapeutic strategy.

A key and unexpected finding was the immune mechanism underlying EVT0185's efficacy. Transcriptomic and spatial profiling in mice and human patient samples showed that reduced ACLY activity in tumors was linked to significant upregulation of the chemokine CXCL13, increased infiltration of B cells, and formation of tertiary lymphoid structures (TLS) — organized immune aggregates associated with improved anti-tumor immunity. Depletion of B cells completely abolished the anti-tumor effects of ACLY inhibition, confirming that the immunological remodeling is essential to the drug's mechanism of action, not merely a secondary effect.

These results reframe ACLY inhibition as not simply an anti-proliferative strategy but as a means to reshape the immunosuppressive MASH-HCC microenvironment. The study bridges tumor metabolism and immune regulation, suggesting that metabolic reprogramming can unlock immune responses in cancers that are otherwise resistant to immunotherapy. Clinical translation of EVT0185 is supported by its oral bioavailability, targeted hepatic activation, and favorable combination potential.