2. Academic Validation
  3. ACLY inhibition promotes tumour immunity and suppresses liver cancer

ACLY inhibition promotes tumour immunity and suppresses liver cancer

  • Nature. 2025 Sep;645(8080):507-517. doi: 10.1038/s41586-025-09297-0.
Jaya Gautam # 1 2,  Jianhan Wu # 1 2,  James S V Lally # 1 2,  Jamie D McNicol 3,  Russta Fayyazi 1,  Elham Ahmadi 1 4,  Daniela Carmen Oniciu 2 5,  Spencer Heaton 2,  Roger S Newton 2,  Sonia Rehal 1,  Dipankar Bhattacharya 6,  Fiorella Di Pastena 1 2,  Binh Nguyen 7 8,  Celina M Valvano 1,  Logan K Townsend 1,  Suhrid Banskota 1,  Battsetseg Batchuluun 1,  Maria Joy Therese Jabile 1,  Alice Payne 1,  Junfeng Lu 1,  Eric M Desjardins 1,  Naoto Kubota 9,  Evangelia E Tsakiridis 1,  Bejal Mistry 1,  Alex Aganostopoulos 1,  Vanessa Houde 1,  Ann Dansercoer 10 11,  Koen H G Verschueren 10 11,  Savvas N Savvides 10 11,  Joanne A Hammill 3,  Ksenia Bezverbnaya 3,  Paola Muti 1 4,  Theodoros Tsakiridis 1 4,  Wenting Dai 12,  Lei Jiang 12,  Yujin Hoshida 9,  Mark Larché 7 8 13,  Jonathan L Bramson 3,  Scott L Friedman 6,  Kenneth Verstraete 10 11,  Dongdong Wang 1,  Gregory R Steinberg 14 15
Affiliations

Affiliations

  • 1 Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
  • 2 Espervita Therapeutics, Ann Arbor, MI, USA.
  • 3 McMaster Immunology Research Centre, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
  • 4 Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
  • 5 Department of Chemistry, University of Florida, Gainesville, FL, USA.
  • 6 Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 7 Division of Clinical Immunology and Allergy, McMaster Immunology Research Centre, Schroeder Allergy and Immunology Research Institute, McMaster University, Hamilton, Ontario, Canada.
  • 8 Division of Respirology, McMaster Immunology Research Centre, Schroeder Allergy and Immunology Research Institute, McMaster University, Hamilton, Ontario, Canada.
  • 9 Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 10 Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.
  • 11 Unit for Structural Biology, VIB Center for Inflammation Research, Ghent, Belgium.
  • 12 Department of Molecular and Cellular Endocrinology, Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, CA, USA.
  • 13 Firestone Institute for Respiratory Health, The Research Institute at St. Joe's, St. Joseph's Healthcare, Hamilton, Ontario, Canada.
  • 14 Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. gsteinberg@mcmaster.ca.
  • 15 Espervita Therapeutics, Ann Arbor, MI, USA. gsteinberg@mcmaster.ca.
  • # Contributed equally.
PMID: 40739358 DOI: 10.1038/s41586-025-09297-0
Abstract

Immunosuppressive tumour microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC) (MASH-HCC)1-3. Although immune cell metabolism influences effector function, the effect of tumour metabolism on immunogenicity is less understood4. ATP Citrate Lyase (ACLY) links substrate availability and Mitochondrial Metabolism with lipid biosynthesis and gene regulation5-7. Although ACLY inhibition shows antiproliferative effects in various tumours, clinical translation has been limited by challenges in inhibitor development and compensatory metabolic pathways8-12. Here, using a mouse model of MASH-HCC that mirrors human disease, genetic inhibition of ACLY in hepatocytes and tumours reduced neoplastic lesions by over 70%. To evaluate the therapeutic potential of this pathway, a novel small-molecule ACLY inhibitor, EVT0185 (6-[4-(5-carboxy-5-methyl-hexyl)-phenyl]-2,2-dimethylhexanoic acid), was identified via phenotypic screening. EVT0185 is converted to a CoA thioester in the liver by SLC27A2 and structural analysis by cryo-electron microscopy reveals that EVT0185-CoA directly interacts with the CoA-binding site of ACLY. Oral delivery of EVT0185 in three mouse models of MASH-HCC dramatically reduces tumour burden as monotherapy and enhances efficacy of current standards of care including tyrosine kinase inhibitors and immunotherapies. Transcriptomic and spatial profiling in mice and humans linked reduced tumour ACLY with increases in the chemokine CXCL13, tumour-infiltrating B cells and tertiary lymphoid structures. The depletion of B cells blocked the antitumour effects of ACLY inhibition. Together, these findings illustrate how targeting tumour metabolism can rewire immune function and suppress Cancer progression in MASH-HCC.

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