Gautam Jaya, Wu Jianhan, Lally James S V, McNicol Jamie D, Fayyazi Russta, Ahmadi Elham, Oniciu Daniela Carmen, Heaton Spencer, Newton Roger S, Rehal Sonia, Bhattacharya Dipankar, Di Pastena Fiorella, Nguyen Binh, Valvano Celina M, Townsend Logan K, Banskota Suhrid, Batchuluun Battsetseg, Jabile Maria Joy Therese, Payne Alice, Lu Junfeng, Desjardins Eric M, Kubota Naoto, Tsakiridis Evangelia E, Mistry Bejal, Aganostopoulos Alex, Houde Vanessa, Dansercoer Ann, Verschueren Koen H G, Savvides Savvas N, Hammill Joanne A, Bezverbnaya Ksenia, Muti Paola, Tsakiridis Theodoros, Dai Wenting, Jiang Lei, Hoshida Yujin, Larché Mark, Bramson Jonathan L, Friedman Scott L, Verstraete Kenneth, Wang Dongdong, Steinberg Gregory R
Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Espervita Therapeutics, Ann Arbor, MI, USA.
Nature. 2025 Jul 30. doi: 10.1038/s41586-025-09297-0.
Immunosuppressive tumour microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC) (MASH-HCC). Although immune cell metabolism influences effector function, the effect of tumour metabolism on immunogenicity is less understood. ATP citrate lyase (ACLY) links substrate availability and mitochondrial metabolism with lipid biosynthesis and gene regulation. Although ACLY inhibition shows antiproliferative effects in various tumours, clinical translation has been limited by challenges in inhibitor development and compensatory metabolic pathways. 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.
免疫抑制性肿瘤微环境在诸如代谢功能障碍相关脂肪性肝炎（MASH）驱动的肝细胞癌（HCC）（MASH-HCC）等癌症中很常见。尽管免疫细胞代谢会影响效应功能，但肿瘤代谢对免疫原性的影响却鲜为人知。ATP柠檬酸裂解酶（ACLY）将底物可用性和线粒体代谢与脂质生物合成及基因调控联系起来。尽管ACLY抑制在各种肿瘤中显示出抗增殖作用，但临床转化受到抑制剂开发和代偿性代谢途径方面挑战的限制。在此，利用一种反映人类疾病的MASH-HCC小鼠模型，肝细胞和肿瘤中ACLY的基因抑制使肿瘤性病变减少了70%以上。为了评估该途径的治疗潜力，通过表型筛选鉴定出一种新型小分子ACLY抑制剂EVT0185（6-[4-(5-羧基-5-甲基己基)-苯基]-2,2-二甲基己酸）。EVT0185在肝脏中被SLC27A2转化为CoA硫酯，冷冻电子显微镜结构分析表明EVT0185-CoA直接与ACLY的CoA结合位点相互作用。在三种MASH-HCC小鼠模型中口服EVT0185作为单一疗法可显著减轻肿瘤负担，并增强包括酪氨酸激酶抑制剂和免疫疗法在内的当前护理标准的疗效。小鼠和人类的转录组学及空间分析表明，肿瘤ACLY的减少与趋化因子CXCL13、肿瘤浸润B细胞和三级淋巴结构的增加有关。B细胞的耗竭阻断了ACLY抑制的抗肿瘤作用。总之，这些发现说明了靶向肿瘤代谢如何重塑免疫功能并抑制MASH-HCC中的癌症进展。
