Immune checkpoint inhibitors like anti-PD-1 have transformed melanoma treatment, yet more than half of patients fail to respond or eventually develop resistance. The tumor microenvironment and the gut microbiome are increasingly recognized as critical determinants of immunotherapy outcomes. Melanoma patients often show reduced levels of beneficial gut bacteria, including Bifidobacterium, and lower microbial diversity. While fecal microbiota transplants from responders have restored sensitivity in some non-responders, the precise bacterial species and their active metabolites responsible for this effect have remained unclear. Given these challenges, there is an urgent need to identify specific microbial factors that can safely enhance anti-tumor immunity and improve immunotherapy responses.
Researchers from Southern Medical University in Guangzhou, China, publishing (DOI: 10.20892/j.issn.2095-3941.2025.0652)in the May 2026 issue of Cancer Biology & Medicine, have discovered that Bifidobacterium animalis—a probiotic commonly found in fermented dairy products—produces mannose, which activates CD8⁺ T cells and suppresses melanoma progression in mouse models. The study reveals a novel gut-microbiome-immune axis that could lead to new adjuvant strategies for melanoma immunotherapy. The work was supported by the National Natural Science Foundation of China and the Guangzhou Science and Technology Project.
The research team isolated five Bifidobacterium species from healthy human stool and screened them for anti-cancer activity. B. animalis stood out as the most potent inhibitor of melanoma cell growth in culture. When given orally to mice with B16-F10 melanoma tumors, the bacterium significantly reduced tumor volume and weight—without ever colonizing the tumor tissue itself, indicating that its effects were mediated entirely through secreted metabolites.
Using size fractionation and metabolomics, the team identified mannose as the key bioactive molecule—a small, non-protein compound under 3 kilodaltons. In mice, drinking water supplemented with 1% mannose replicated the anti-tumor effects of the live probiotic, increasing tumor-infiltrating CD8⁺ T cells and boosting their production of killer molecules like granzyme B (GZMB), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α).
Mechanistically, mannose enters CD8⁺ T cells through the GLUT1 (glucose transporter 1) and activates the Hippo signaling pathway. This leads to phosphorylation and cytoplasmic retention of YAP1—a transcription factor that normally suppresses T-cell effector function. By preventing YAP1 from entering the nucleus, mannose removes a critical brake on T-cell cytotoxicity. When combined with anti-PD-1 therapy, B. animalis produced a synergistic effect, substantially improving tumor control compared to either treatment alone.
"We were surprised to find that a simple sugar like mannose could have such a profound effect on T-cell immunity," the authors said. "What's exciting is that mannose doesn't just activate T cells—it does so by targeting a specific molecular pathway, the Hippo-YAP1 axis, that has not been previously linked to microbial metabolites in cancer immunotherapy. This gives us a clear mechanistic roadmap for how a gut bacterium can systemically influence anti-tumor immunity. The fact that mannose also enriches other beneficial gut bacteria suggests a dual benefit: it directly empowers immune cells while simultaneously fostering a more favorable microbial ecosystem."
The findings open several translational avenues. B. animalis is already widely consumed as a probiotic with an established safety record, making it a potentially attractive adjunct to existing immunotherapies. Oral mannose supplementation, which is well-tolerated in humans, could offer a simpler and more standardized approach than live bacteria. The study also highlights the Hippo-YAP1 pathway as a new therapeutic target for enhancing T-cell function in cancer. Future clinical studies will be needed to validate these findings in melanoma patients and to determine optimal dosing strategies. If confirmed, this probiotic-metabolite approach could provide a safe, low-cost strategy to overcome resistance to immune checkpoint blockade and improve outcomes for the many patients who currently do not benefit from these therapies.
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References
DOI
10.20892/j.issn.2095-3941.2025.0652
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0652
Funding information
This study was supported by the National Natural Science Foundation of China (Grant No. 82403246) and the Guangzhou Science and Technology Project (Grant No. 2025A04J4030).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 12.4), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).