Microbial Metabolic Pathways Guide Response to Immune Checkpoint Blockade Therapy

作者：Iris Mimpen, Thomas Battaglia, Miguel Parra-Martinez, Catherine Toner-Bartelds, Laurien J. Zeverijn, Birgit S. Geurts, Karlijn Verkerk, Louisa R. Hoes, Allard W. J. van Renterghem, Michaël Noë, Ingrid Hofland, Annegien Broeks, Vincent van der Noort, Edwin C.A. Stigter, Can Gulersonmez, Boudewijn Burgering, Merel van Gogh, Marcel R. de Zoete, Hans Gelderblom, Krijn K. Dijkstra, Lodewyk F.A. Wessels, Emile E. Voest · 发表于：Cancer Discovery · 年份：2025 · DOI：10.1158/2159-8290.cd-24-1669 · 被引用次数：7 · 研究领域：Cancer Research and Treatments、Immune cells in cancer、Cancer Immunotherapy and Biomarkers

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 from ICB-treated patients, we showed that community-level metabolic pathways are stable across individuals, making them suitable for predicting ICB response. We identified several microbial metabolic processes significantly associated with response, including the methylerythritol 4-phosphate (MEP) pathway, which was associated with response and induced Vδ2 T cell-mediated antitumor 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 cross-talk. SIGNIFICANCE: Microbial metabolic pathways are highly conserved across individuals and therefore offer an opportunity to link the microbiome to immunotherapy efficacy. We identified specific microbial metabolic pathways associated with response to ICB and provided mechanistic ...