Chemotherapy modulation by a cancer-associated microbiota metabolite

Daniel Martinez-Martinez*, Tanara V Peres*, Kristin Gehling*, Leonor Quintaneiro, Cecilia Cabrera, Maksym Cherevatenko, Stephen J Cutty, Lena Best, Georgios Marinos, Johannes Zimmerman, Ayesha Safoor, Despoina Chrysostomou, Joao B Mokochinski, Alex Montoya, Susanne Brodesser, Michalina Zatorska, Timothy Scott, Ivan Andrew, Holger Kramer, Masuma Begum, Bian Zhang, Bernard T Golding, Julian R Marchesi, Susumu Hirabayashi, Christoph Kaleta, Alexis R Barr, Christian Frezza, Helena M Cochemé, Filipe Cabreiro. Chemotherapy modulation by a cancer-associated microbiota metabolite. Cell Systems, volume 16, issue 9, pages 101397 (2025). doi: 10.1016/j.cels.2025.101397. *These authors contributed equally to this work.

Understanding how the microbiota produces regulatory metabolites is of significance for cancer and cancer therapy. Using a host-microbe-drug-nutrient 4-way screening approach, we evaluated the role of nutrition at the molecular level in the context of 5-fluorouracil toxicity. Notably, our screens identified the metabolite 2-methylisocitrate, which was found to be produced and enriched in human tumor-associated microbiota. 2-methylisocitrate exhibits anti-proliferative properties across genetically and tissue-diverse cancer cell lines, three-dimensional (3D) spheroids, and an in vivo Drosophila gut tumor model, where it reduced tumor dissemination and increased survival. Chemical landscape interaction screens identified drug-metabolite signatures and highlighted the synergy between 5-fluorouracil and 2-methylisocitrate. Multi-omic analyses revealed that 2-methylisocitrate acts via multiple cellular pathways linking metabolism and DNA damage to regulate chemotherapy. Finally, we converted 2-methylisocitrate into its trimethyl ester, thereby enhancing its potency. This work highlights the great impact of microbiome-derived metabolites on tumor proliferation and their potential as promising co-adjuvants for cancer treatment.