{"title":"Orlistat facilitates immunotherapy via AKT-FOXO3a-FOXM1-mediated PD-L1 suppression.","authors":"Qingyun Tang, Jie Li, Lianhua Zhang, Shuo Zeng, Qiyu Bao, Weichao Hu, Lijiao He, Guiping Huang, Liting Wang, Yunyi Liu, Xiaoyan Zhao, Shiming Yang, Changjiang Hu","doi":"10.1136/jitc-2024-008923","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The immunotherapy targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death ligand-1 (PD-L1) has achieved significant breakthroughs, but further improvements are still needed in cancer treatment.</p><p><strong>Methods: </strong>We investigated orlistat, a drug approved by the Food and Drug Administration for the treatment of obesity and found that it can enhance the efficacy of CTLA-4 blockade immunotherapy. We conducted both in vivo and in vitro experiments to explore the mechanism by which orlistat increased antitumor immunity.</p><p><strong>Results: </strong>Orlistat enhances the efficacy of anti-CTLA-4 immunotherapy by suppressing tumor cell PD-L1 protein expression and boosting the transcription of interferon-stimulated genes (ISGs) and MHC-I. Mechanistically, orlistat inhibits AKT activity and subsequent phosphorylation of forkhead box O3a (FOXO3a) at its threonine (T) 32, serine (S) 253, thereby downregulating Forkhead box M1 (FOXM1) expression, which ultimately suppresses PD-L1 transcription. Specifically, inhibition of FOXM1 leads to FOXO3a accumulation through impaired AKT activity. FOXM1 activates protein kinase B (AKT) via acting as a scaffold to facilitate 3-phosphoinositide-dependent protein kinase 1 (PDK1) and AKT and interaction. In addition, orlistat enhances phosphorylated signal transducer and activator of transcription 1 (p-STAT1) at tyrosine (Y) 701, resulting in upregulation of ISGs and MHC-I.</p><p><strong>Conclusions: </strong>Orlistat plays a crucial role in modulating the immune response and supporting the combination with CTLA-4 blockade to promote antitumor immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3000,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951015/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal for Immunotherapy of Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jitc-2024-008923","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: The immunotherapy targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death ligand-1 (PD-L1) has achieved significant breakthroughs, but further improvements are still needed in cancer treatment.
Methods: We investigated orlistat, a drug approved by the Food and Drug Administration for the treatment of obesity and found that it can enhance the efficacy of CTLA-4 blockade immunotherapy. We conducted both in vivo and in vitro experiments to explore the mechanism by which orlistat increased antitumor immunity.
Results: Orlistat enhances the efficacy of anti-CTLA-4 immunotherapy by suppressing tumor cell PD-L1 protein expression and boosting the transcription of interferon-stimulated genes (ISGs) and MHC-I. Mechanistically, orlistat inhibits AKT activity and subsequent phosphorylation of forkhead box O3a (FOXO3a) at its threonine (T) 32, serine (S) 253, thereby downregulating Forkhead box M1 (FOXM1) expression, which ultimately suppresses PD-L1 transcription. Specifically, inhibition of FOXM1 leads to FOXO3a accumulation through impaired AKT activity. FOXM1 activates protein kinase B (AKT) via acting as a scaffold to facilitate 3-phosphoinositide-dependent protein kinase 1 (PDK1) and AKT and interaction. In addition, orlistat enhances phosphorylated signal transducer and activator of transcription 1 (p-STAT1) at tyrosine (Y) 701, resulting in upregulation of ISGs and MHC-I.
Conclusions: Orlistat plays a crucial role in modulating the immune response and supporting the combination with CTLA-4 blockade to promote antitumor immunotherapy.
期刊介绍:
The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.