Iris L Mimpen,Thomas W Battaglia,Miguel Parra Martinez,Catherine Toner-Bartelds,Laurien J Zeverijn,Birgit S Geurts,Karlijn Verkerk,Louisa R Hoes,Allard W J van Renterghem,Michael Noe,Ingrid Hofland,Annegien Broeks,Vincent van der Noort,Edwin C A Stigter,Can M C Gulersonmez,Boudewijn M T Burgering,Merel van Gogh,Marcel R de Zoete,Hans Gelderblom,Krijn K Dijkstra,Lodewyk F A Wessels,Emile E Voest
{"title":"Microbial metabolic pathways guide response to immune checkpoint blockade therapy.","authors":"Iris L Mimpen,Thomas W Battaglia,Miguel Parra Martinez,Catherine Toner-Bartelds,Laurien J Zeverijn,Birgit S Geurts,Karlijn Verkerk,Louisa R Hoes,Allard W J van Renterghem,Michael Noe,Ingrid Hofland,Annegien Broeks,Vincent van der Noort,Edwin C A Stigter,Can M C Gulersonmez,Boudewijn M T Burgering,Merel van Gogh,Marcel R de Zoete,Hans Gelderblom,Krijn K Dijkstra,Lodewyk F A Wessels,Emile E Voest","doi":"10.1158/2159-8290.cd-24-1669","DOIUrl":null,"url":null,"abstract":"Studies have identified a link between specific microbiome-derived bacteria and immune checkpoint blockade (ICB) efficacy. However, these species lack consistency across studies and their immunomodulatory mechanisms remain elusive. To understand the influence of the microbiome on ICB response we studied its functional capacity. Using pan-cancer metagenomics data of ICB-treated patients, we showed that community-level metabolic pathways are stable across individuals, making them suitable to predict ICB response. We identified several microbial metabolic processes significantly associated with response, including the methylerythritol phosphate (MEP) pathway, which was associated with response and induced Vδ2 T cell-mediated anti-tumor responses in patient-derived tumor organoids. In contrast, riboflavin synthesis was associated with ICB resistance, and its intermediates induced mucosal-associated invariant T (MAIT) cell-mediated immune suppression. Moreover, gut metabolomics revealed that high riboflavin levels were linked to worse survival in patients with abundant intratumoral MAIT cells. Collectively, our results highlight the relevance of metabolite-mediated microbiome-immune cell crosstalk.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"41 1","pages":""},"PeriodicalIF":33.3000,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.cd-24-1669","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Studies have identified a link between specific microbiome-derived bacteria and immune checkpoint blockade (ICB) efficacy. However, these species lack consistency across studies and their immunomodulatory mechanisms remain elusive. To understand the influence of the microbiome on ICB response we studied its functional capacity. Using pan-cancer metagenomics data of ICB-treated patients, we showed that community-level metabolic pathways are stable across individuals, making them suitable to predict ICB response. We identified several microbial metabolic processes significantly associated with response, including the methylerythritol phosphate (MEP) pathway, which was associated with response and induced Vδ2 T cell-mediated anti-tumor responses in patient-derived tumor organoids. In contrast, riboflavin synthesis was associated with ICB resistance, and its intermediates induced mucosal-associated invariant T (MAIT) cell-mediated immune suppression. Moreover, gut metabolomics revealed that high riboflavin levels were linked to worse survival in patients with abundant intratumoral MAIT cells. Collectively, our results highlight the relevance of metabolite-mediated microbiome-immune cell crosstalk.
期刊介绍:
Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.