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Summary of Cell Systems. https://doi.org/10.1016/j.cels.2025.101397
Dr. Daniel Martinez-Martinez et al.
Points
- A novel 4-way screen identified 2-methylisocitrate as a key regulator of 5-fluorouracil activity.
- This metabolite, found in tumor-associated microbiota, exhibited strong anti-proliferative effects across diverse cancer models.
- Synergistic interactions between 2-methylisocitrate and 5-fluorouracil were discovered through chemical screens.
- Multi-omic analyses confirmed that 2-methylisocitrate regulates chemotherapy by influencing cellular metabolism and DNA damage pathways.
- Modification of 2-methylisocitrate into a trimethyl ester led to a notable enhancement in its therapeutic potency.
Summary
This research investigated the impact of microbiota-produced metabolites on cancer and chemotherapy, specifically focusing on 5-fluorouracil (5-FU) toxicity. A host-microbe-drug-nutrient 4-way screening approach identified 2-methylisocitrate, a metabolite enriched in human tumor-associated microbiota. This metabolite demonstrated anti-proliferative effects across various cancer cell lines, 3D spheroids, and an in vivo Drosophila gut tumor model, where it significantly reduced tumor dissemination and enhanced survival.
Chemical landscape interaction screens revealed synergistic effects between 5-FU and 2-methylisocitrate. Multi-omic analyses indicated that 2-methylisocitrate influences multiple cellular pathways, linking metabolism and DNA damage to regulate chemotherapy response. The study also successfully converted 2-methylisocitrate into its trimethyl ester, resulting in enhanced therapeutic potency.
These findings underscore the substantial influence of microbiome-derived metabolites on tumor proliferation and suggest their potential as effective co-adjuvants in cancer treatment. The research highlights the intricate interplay between host, microbiota, drug, and nutrition, paving the way for novel therapeutic strategies.
Link to the article: https://www.cell.com/cell-systems/fulltext/S2405-4712(25)00230-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2405471225002303%3Fshowall%3Dtrue
References
Martinez-Martinez, D., Peres, T. V., Gehling, K., Quintaneiro, L., Cabrera, C., Cherevatenko, M., Cutty, S. J., Best, L., Marinos, G., Zimmerman, J., Safoor, A., Chrysostomou, D., Mokochinski, J. B., Montoya, A., Brodesser, S., Zatorska, M., Scott, T., Andrew, I., Kramer, H., … Cabreiro, F. (2025). Chemotherapy modulation by a cancer-associated microbiota metabolite. Cell Systems, 101397. https://doi.org/10.1016/j.cels.2025.101397
