Abstract 2212: Microbial metabolic pathways guide response to immune checkpoint blockade therapy

Abstract Recent 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. We hypothesized that community-level metabolic pathways across microbes are more suitable to predict ICB response. Using a curated resource of pan-cancer metagenomics data of ICB-treated patients, we identified several microbial metabolic processes significantly associated with response. Methylerythritol phosphate (MEP) pathway activity was associated with response and intratumoral Vδ2 T cell infiltration and induced Vδ2 T cell-mediated anti-tumor responses in patient-derived tumor organoids. In contrast, the riboflavin pathway was associated with ICB resistance, and its intermediates led to mucosal-associated invariant T (MAIT) cell-mediated immune suppression. Collectively, our results highlight the relevance and complexity of metabolite-mediated microbiome-immune crosstalk. Citation Format: Iris L. Mimpen, Thomas W. Battaglia, Miguel Parra Martinez, Laurien J. Zeverijn, Birgit S. Geurts, Louisa R. Hoes, Vincent van der Noort, Hans Gelderblom, Krijn K. Dijkstra, Lodewyk F. Wessels, Emile E. Voest. Microbial metabolic pathways guide response to immune checkpoint blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2212.