Gut microbiome key to immunotherapy success: new “Cell” study reveals mechanisms of individual molecules

The study centered on an observational cohort of 129 patients from three German university hospitals in Munich (LMU), Heidelberg, and Regensburg. Using advanced microbiome and metabolome analyses, the research team identified gut-microbiome metabolites associated with either response to or failure of CAR T-cell therapy. The metabolites were then tested experimentally in mouse models and in preclinical models using human CAR T cells. This made it possible to analyze their direct effects on CAR T-cell activity, metabolism, and efficacy, and to clarify the underlying biological mechanisms in greater detail for the first time. “Our results show that individual microbial metabolites can have very different effects and therefore need to be considered specifically if the gut microbiome is to be used in the future to predict or improve treatment success,” says Prof. Hendrik Poeck, head of the LIT Collaborative Group “Innate Immune Sensing in Cancer and Transplantation” and senior physician in the Department of Internal Medicine III (Hematology and Oncology) at University Hospital Regensburg. The Leibniz Institute for Immunotherapy (LIT), a member of the Leibniz Association, is closely linked to the University of Regensburg and University Hospital Regensburg through joint professorships and collaborative projects.

Particularly notable is the short-chain fatty acid valerate: Low levels before treatment were associated with a higher risk of disease progression, whereas therapeutic administration improved CAR T-cell function in human and murine models. By contrast, elevated levels of indole metabolites such as indole-3-carboxaldehyde and indole-3-acetic acid were linked to unfavorable outcomes; functionally, these metabolites reduced CAR T-cell efficacy in both human and mouse models. Isovalerate, a branched-chain fatty acid, proved more complex: It improved CAR T-cell function in some respects, but was also associated with a previously unknown tumor-promoting effect.

Microbiome complexity: effects on both the immune system and the tumor

The study offers a new perspective on the role of the gut microbiome in CAR T-cell therapy. Until now, research has focused primarily on bacterial composition. This work shows instead that microbial metabolites are the key biological actors influencing treatment success. Importantly, the study also demonstrates that these metabolites are not inherently beneficial or harmful; rather, they can produce highly specific and sometimes opposing effects. “These findings highlight the ambivalence and complexity of the microbiome: It affects not only the therapeutic immune system, but also the tumor itself,” Poeck says.

“With our study, we challenge a previously dominant view and open up new perspectives for microbiome research and the further development of microbiome-based therapies,” says Dr. Dr. Markus Perl, first author and physician at University Hospital Regensburg. In the long term, the results could help improve immunotherapy outcomes through targeted modulation of the gut microbiome, for example by microbiota transfer or specific dietary strategies.

“Based on these findings, we are currently preparing a clinical trial, CARBiome, within the NCT-OCT2 program on microbiota transfer in patients with multiple myeloma who have previously received antibiotics and are scheduled to undergo CAR T-cell therapy,” says Dr. Erik Thiele-Orberg, Ph.D., co-last author of the study and senior physician in the Department of Internal Medicine III at University Hospital Regensburg. Perl adds that the study also shows “that excellent, internationally visible cutting-edge research at the Regensburg science hub is successful thanks to strong collaborations and the joint efforts of many dedicated scientists worldwide.”

Microbiome research shifts toward biologically active metabolites

The study was conducted in close collaboration across multiple sites and was supported by the Bavarian Center for Cancer Research (BZKF; “Translational Groups” program), the Leibniz Institute for Immunotherapy (LIT), the German Cancer Aid Excellence Program, an ERC Consolidator Grant (“MICROBOTS”), the Wilhelm Sander Foundation, and the German Research Foundation (DFG; SFB 1371 and SFB/TRR 221). Participating institutions included the BZKF sites in Regensburg, Würzburg, and Munich (LMU), as well as the National Center for Tumor Diseases (NCT) WERA and the NCT sites in Heidelberg and Tübingen. The work also involved international partners from the United States and France.

“These findings shift microbiome research in CAR T-cell therapy away from a purely compositional view of bacteria and toward biologically active metabolites,” explain Dr. Severin Gütter and Dr. Simon Holzinger, both co-first authors of the study and researchers of the LIT collaboration group. “We hope that focusing on bacterial metabolites will enable more robust biomarkers for the treatment success in the future. Furthermore, the targeted therapeutic use of these metabolites opens up interesting perspectives for future treatments, for example, to make CAR T-cell therapy more effective.”

The study team has already provided an initial proof of concept for the clinical application: a metabolite-based risk score predicted clinical response to CAR T-cell therapy. The next step is to validate these findings in additional cohorts in collaboration with national and international partners.

For more information, please visit the full article in the journal “Cell”:

Perl et al., Opposing functions of gut immunomodulatory metabolites on CAR-T therapy, Cell (2026), https://doi.org/10.1016/j.cell.2026.09.004