# Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint

## TL;DR

This paper shows that inhibiting ACAT, a cholesterol-related enzyme, can fight hepatitis B and liver cancer while reviving immune cells.

## Contribution

ACAT inhibition is revealed as a novel metabolic checkpoint that simultaneously targets viruses, tumors, and exhausted T cells.

## Key findings

- ACAT inhibition reduces lipid droplets in T cells and enhances their signaling and energy.
- ACAT inhibitors rescue dysfunctional T cells from human liver and tumor tissue ex vivo.
- ACAT inhibition reduces HBV particles and boosts T cell responses to PD-1 blockade.

## Abstract

Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8+ T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8+ T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC.

Shared metabolic pathways could allow simultaneous manipulation of T cells, viruses and tumours. Here the authors show targeting cholesterol esterification restrains hepatitis B in vitro, whilst bolstering exhausted antigen-specific T cell responses from human liver and hepatocellular carcinoma.