ACLY inhibition promotes tumour immunity and suppresses liver cancer

Targeting ACLY-mediated lipogenesis in MASH-HCC enhances B cell-mediated antitumor immunity

The incidence of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC) is rising worldwide, driven by lifestyle-related cardiometabolic risk factors. There is clear evidence from mouse models of MASH-HCC that the etiology of HCC can shape the antitumor immune response and influence the results from checkpoint therapy regimen (DOI: 10.1038/s41586-021-03362-0). While precise definitions for MASH-HCC are lacking in published prospective clinical trials of checkpoint therapy, patients with viral etiology tend to have better responses than non-viral etiology patients, which includes patients with MASH-HCC (DOI: 10.1158/1078-0432.ccr-21-1258). However, the mechanisms linking metabolism, carcinogenesis, and antitumor immune responses remain poorly understood. A recently published study by Gautam et al. sheds light on the role of lipogenesis in HCC. The authors focused on ATP-citrate lyase (ACLY), a key metabolic enzyme that supports lipogenesis through its role in the citrate shuttle for the generation of cytosolic acetyl-CoA. The authors used a murine model combining chemical carcinogenesis (using diethylnitrosamine [DEN]) and high-fat, high-fructose “Western” diet (WD-DEN) to mimic human MASH-HCC. Control models included DEN alone and DEN-CCl4. The authors observed broad ACLY expression and the major histological hallmarks of MASH-HCC, such as macrovesicular and microvesicular steatosis, ballooning, Mallery-Denk bodies, and lymphocytic infiltration. In hepatocyte-targeted Acly knockout mice, the authors observed a marked reduction in ACLY expression, fatty acid levels, and tumor numbers, consistent with prior findings. 
The authors performed a phenotypic screen in primary mouse hepatocytes. This led to the discovery of EVT0185, a small-molecule prodrug converted by SLC27A2-expressing cells (expressed in hepatocytes but not significantly in immune cells) into the active EVT0185-CoA thioester, which inhibits ACLY. EVT0185 effectively suppressed MASH-HCC development in the murine model and synergized with checkpoint blockade therapy (anti-PD-L1 and anti-VEGFR). 
Multiplexed imaging analysis and single-cell and spatial transcriptomics revealed that ACLY inhibition induced the chemokine CXCL13 and promoted B-cell, particularly plasma cell, enrichment within the tumor microenvironment. Depletion studies demonstrated that B cells were essential for mediating tumor suppression. Indeed, Acly-deficient cancer cells proliferated unrestrained in immunodeficient hosts, indicating that the antitumor effect of ACLY arises from the recruitment of B cell-mediated responses rather than direct inhibition of cancer growth or cytotoxicity.
The study highlights a metabolic link between lipogenesis in HCC cells and immunoregulation. This pathway is associated with MASH-HCC models and resembles features observed in human MASH-HCC. However, the study is inconclusive with respect to whether the mechanism is specific to MASH-HCC. Indeed, ACLY is also expressed in non-MASH HCC, suggesting that it may represent a broader therapeutic target across HCC etiologies. Indeed, previous Acly-focused studies in non-MASH HCC models have implicated ACLY inhibition in modulating resistance to tyrosine kinase inhibitor (TKI) therapy (e.g., DOI: 10.7150/jca.52778). 
Targeting metabolic enzymes that are central to all human cells carries the risk of significant off-target effects. In particular, ACLY plays a critical role in supporting T-cell effector responses (DOI: 10.1084/jem.20231820). The development of a small-molecule ACLY inhibitor that, as a prodrug, is selectively activated in hepatocytes—but not in immune cells—via SLC27A2-dependent conversion offers a promising strategy for reducing off-target toxicity. The study also puts B cells into focus as potential mediators of antitumor activity in HCC. Interestingly, despite the observed synergy with T-cell dependent checkpoint therapy, the authors did not report a prominent role for T-cell responses following ACLY inhibition in their model. Of note, B cells have been identified as components of immune architecture neighborhoods enriched with CD8+ T cells, which are associated with improved responses to checkpoint therapy in patients (DOI: 10.1136/gutjnl-2024-332837). They are also found within tertiary lymphoid structures associated with therapeutic response in HCC (DOI: 10.1101/2023.10.16.562104). The authors did not investigate the contribution of B-cell interactions with T cells or other immune cells in further detail. It thus remains unclear how B cells mechanistically contribute to antitumor effects downstream of ACLY inhibition. The observed enrichment of plasma cells raises the possibility that local immunoglobulin production may be involved. Further studies are warranted to delineate the mediators of the immunosensitizing effect. Collectively, the findings reveal a cancer cell metabolism–immune crosstalk in MASH-HCC—that may be exploited to enhance tumor responsiveness to immunotherapy.