A collaborative research team from CRC TRR 221 and leading German CAR-T cell treatment centers has discovered that metabolites produced by the gut microbiome can significantly influence the effectiveness of CAR-T cell therapy. The study, led by first author Markus Perl (UR), senior authors Erik Thiele Orberg (UKR) and CRC TRR 221 scientist Hendrik Poeck, provides new insights into how the intestinal microbiome may be harnessed to improve outcomes for patients with hematological malignancies.
CAR-T cell therapy has transformed the treatment of relapsed or refractory blood cancers, including lymphoma, leukemia and multiple myeloma. However, many patients still experience disease progression, making it essential to identify factors that influence treatment success.
In this multicenter study, researchers analyzed samples from 129 patients treated with CAR-T cell therapy across three German centers. Using shotgun metagenomic sequencing and targeted metabolomics, they investigated both the gut microbiome and the metabolites produced by intestinal bacteria.
The researchers found that microbial metabolites were stronger predictors of treatment outcome than individual bacterial species. Higher levels of the short-chain fatty acid valeric acid before CAR-T cell therapy were associated with improved progression-free survival, whereas increased levels of indole-3-carboxaldehyde, indole-3-acetic acid and isovaleric acid were linked to poorer outcomes.
Hendrik Poeck, co-senior author from the University Hospital Regensburg (UKR), believes these findings highlight a new avenue for improving CAR-T cell therapy. “The gut microbiome represents a promising and potentially modifiable component of cancer therapy. Our results suggest that monitoring and manipulating microbial metabolites could become part of personalized approaches to improve CAR-T cell therapy outcomes.”
Functional experiments confirmed that these metabolites directly influence CAR-T cell activity. Valeric acid enhanced CAR-T cell function, while indole-3-carboxaldehyde and isovaleric acid reduced therapeutic efficacy, demonstrating that gut-derived metabolites actively regulate anti-tumor immune responses.
“Our findings show that the functional output of the microbiome—the metabolites it produces—may be more important than simply identifying which bacteria are present,” said Markus Perl, first author of the study. “By identifying metabolites that enhance or impair CAR-T cell function, we have uncovered potential new strategies to optimize immunotherapy before treatment even begins.”
The study also confirmed the negative impact of antibiotic exposure before CAR-T cell infusion. Patients who received antibiotics shortly before treatment showed reduced microbial diversity, lower levels of beneficial microbial metabolites and inferior clinical outcomes, further underscoring the importance of preserving a healthy gut microbiome before CAR-T therapy.
Erik Thiele Orberg, co-senior author of the study, emphasized that uncovering these mechanisms required close interdisciplinary collaboration. “This work was made possible through close cooperation between clinical experts, microbiome researchers, immunologists and computational scientists. Combining patient data with molecular analyses and experimental validation allowed us to move beyond associations and identify mechanisms that could be therapeutically targeted.”
The findings provide a foundation for future microbiome-based interventions, including strategies to increase beneficial metabolites such as valeric acid or reduce harmful microbial signals before CAR-T cell treatment. Through the collaborative efforts of CRC TRR 221 and its clinical and scientific partners, the study advances our understanding of how the microbiome shapes cellular immunotherapy and opens new perspectives for precision cancer medicine.

DOI link:https://doi.org/10.1016/j.cell.2026.09.004

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