Bifidobacteria-derived exopolysaccharide promotes anti-tumor immunity

Rômulo Silva de Oliveira¹, Amy Shupe², Tim Krause³, Timmy Richardo⁴, Christina Ohland⁵, Mahana Sabachvili³, Kirsten Bucher³, Jenny Hetzer⁶, Sebastian Hörner⁷, Daniel Dauch⁸, Mathias Heikenwälder⁹, Christoph Trautwein¹⁰, Alexander N R Weber¹¹, Victoria Klepsch¹², Kathy D McCoy¹³, Lukas F Mager¹⁴

Affiliations

¹ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Department of Internal Medicine I, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany.
² Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
³ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Department of Internal Medicine I, Faculty of Medicine, University of Tübingen, Tübingen, Germany.
⁴ Institute of Immunology, Department of Innate Immunity, University of Tübingen, Tübingen, Germany.
⁵ International Microbiome Centre, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
⁶ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany.
⁷ German Cancer Consortium (DKTK), Partner Site Tübingen, a Partnership Between DKFZ and University Hospital Tübingen, Tübingen, Germany; Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.
⁸ Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany; IFIT Cluster of Excellence EXC 2180 "Image Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany.
⁹ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany; IFIT Cluster of Excellence EXC 2180 "Image Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany.
¹⁰ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany; IFIT Cluster of Excellence EXC 2180 "Image Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany; Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, University Hospital Tübingen, Tübingen, Germany.
¹¹ Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany; Institute of Immunology, Department of Innate Immunity, University of Tübingen, Tübingen, Germany; German Cancer Consortium (DKTK), Partner Site Tübingen, a Partnership Between DKFZ and University Hospital Tübingen, Tübingen, Germany; IFIT Cluster of Excellence EXC 2180 "Image Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany.
¹² Institute for Cell Genetics, Medical University of Innsbruck, Innsbruck, Austria.
¹³ Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address: kathy.mccoy@ucalgary.ca.
¹⁴ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Department of Internal Medicine I, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany; Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; IFIT Cluster of Excellence EXC 2180 "Image Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany. Electronic address: lukas.mager@med.uni-tuebingen.de.

PMID: 40892540
DOI: 10.1016/j.celrep.2025.116223

Bifidobacteria-derived exopolysaccharide promotes anti-tumor immunity

Rômulo Silva de Oliveira et al. Cell Rep. 2025.

. 2025 Sep 1;44(9):116223.

doi: 10.1016/j.celrep.2025.116223. Online ahead of print.

Authors

Affiliations

¹ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Department of Internal Medicine I, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany.
² Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
³ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Department of Internal Medicine I, Faculty of Medicine, University of Tübingen, Tübingen, Germany.
⁴ Institute of Immunology, Department of Innate Immunity, University of Tübingen, Tübingen, Germany.
⁵ International Microbiome Centre, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
⁶ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany.
⁷ German Cancer Consortium (DKTK), Partner Site Tübingen, a Partnership Between DKFZ and University Hospital Tübingen, Tübingen, Germany; Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.
⁸ Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany; IFIT Cluster of Excellence EXC 2180 "Image Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany.
⁹ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany; IFIT Cluster of Excellence EXC 2180 "Image Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany.
¹⁰ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany; IFIT Cluster of Excellence EXC 2180 "Image Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany; Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, University Hospital Tübingen, Tübingen, Germany.
¹¹ Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany; Institute of Immunology, Department of Innate Immunity, University of Tübingen, Tübingen, Germany; German Cancer Consortium (DKTK), Partner Site Tübingen, a Partnership Between DKFZ and University Hospital Tübingen, Tübingen, Germany; IFIT Cluster of Excellence EXC 2180 "Image Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany.
¹² Institute for Cell Genetics, Medical University of Innsbruck, Innsbruck, Austria.
¹³ Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address: kathy.mccoy@ucalgary.ca.
¹⁴ M3 Research Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Department of Internal Medicine I, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany; Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; IFIT Cluster of Excellence EXC 2180 "Image Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany. Electronic address: lukas.mager@med.uni-tuebingen.de.

PMID: 40892540
DOI: 10.1016/j.celrep.2025.116223

Abstract

While several phylogenetically distinct bacterial taxa can predict responses to or improve cancer immunotherapies, the underlying mechanisms remain poorly understood. The use of microbes for microbial therapeutics is currently under intense research, yet safety and regulatory hurdles remain challenging. Thus, non-replicative bacterial-derived molecules or extracts provide promising alternatives. We have identified exopolysaccharides (EPSs) from two bacterial species-Bifidobacterium pseudolongum and Bifidobacterium pseudocatenulatum-that promote anti-tumor immunity. EPS improved Th1 T cell immunity, which was further boosted by the metabolite inosine. Mechanistically, EPS was sensed by dendritic cells in a Tlr2-MyD88-dependent manner, which induced interleukin (IL)-12 and tumor necrosis factor (TNF)-α. Both cytokines were required for T cell-dependent killing of tumor cells in murine colon cancer models. EPS stimulated IL-12 production through Toll-like receptor 2 (TLR2) in human dendritic cells and promoted cell death in patient-derived colon cancer organoids through immune cells. Collectively, our study identifies microbe-derived EPS as an adjuvant immunotherapy in cancer.

Keywords: CP: Cancer; CP: Microbiology; bispecific antibody therapy; checkpoint blockade therapy; exopolysaccharides; germ-free animals; immunity; microbiome; patient-derived organoids dendritic cells.

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Conflict of interest statement

Declaration of interests K.D.M. and L.F.M. have submitted a patent for the use of bacteria in the treatment of cancer, including B. pseudolongum.

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Bifidobacteria-derived exopolysaccharide promotes anti-tumor immunity

Affiliations

Bifidobacteria-derived exopolysaccharide promotes anti-tumor immunity

Authors

Affiliations

Abstract

Conflict of interest statement