Immune checkpoint inhibitors such as anti-PD-1 have revolutionized melanoma treatment, but more than half of patients do not respond or eventually develop resistance. The tumor microenvironment and gut microbiome are increasingly recognized as important determinants of immunotherapy outcomes. Melanoma patients often have reduced levels of beneficial gut bacteria, such as Bifidobacteria, and reduced microbial diversity. Transplantation of fecal microbiota from responders restored susceptibility in some non-responders, but the precise bacterial species and their active metabolites responsible for this effect remain unknown. Considering these challenges, there is an urgent need to identify specific microbial factors that can safely enhance antitumor immunity and improve immunotherapy responses.
Researchers from Southern Medical University in Guangzhou, China published (DOI: 10.20892/j.issn.2095-3941.2025.0652) in the May 2026 issue of the journal. Cancer biology and medicinediscovered it Bifidobacterium animalisMannose, a probiotic commonly found in fermented dairy products, activates CD8+ T cells and inhibits melanoma progression in mouse models. This study reveals a new gut-microbiome-immune axis that may lead to new adjuvant strategies for melanoma immunotherapy. This research was supported by the National Natural Science Foundation of China and the Guangzhou Science and Technology Project.
The research team isolated five species of Bifidobacteria from the stool of healthy humans and screened them for their anti-cancer activity. B.Animals It stands out as the most potent inhibitor of melanoma cell proliferation in culture. Oral administration of this bacterium to mice bearing B16-F10 melanoma tumors significantly reduced tumor volume and weight without colonizing the tumor tissue itself. This indicates that the effect is completely mediated by secreted metabolites.
Using size fractionation and metabolomics, the research team identified mannose as an important bioactive molecule. Mannose is a small non-protein compound less than 3 kilodaltons. In mice, drinking water supplemented with 1% mannose recapitulated the antitumor effects of live probiotics, increasing tumor-infiltrating CD8+ T cells and promoting the production of killer molecules such as granzyme B (GZMB), interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α).
Mechanistically, mannose enters CD8+ T cells via GLUT1 (glucose transporter 1) and activates the Hippo signaling pathway. This phosphorylates and retains YAP1, a transcription factor that normally suppresses T cell effector function, in the cytoplasm. Mannose releases an important brake on T cell cytotoxicity by preventing YAP1 from entering the nucleus. When combined with anti-PD-1 therapy, B.Animals produced a synergistic effect and significantly improved tumor control compared to either treatment alone.
”We were surprised to learn that a simple sugar like mannose can have such a profound impact on T cell immunity.said the authors.Interestingly, mannose not only activates T cells, but also by targeting the Hippo-YAP1 axis, a specific molecular pathway not previously associated with microbial metabolites in cancer immunotherapy. This provides a clear mechanistic roadmap for how gut bacteria systemically influence antitumor immunity. The fact that mannose also enriches other beneficial gut bacteria suggests a dual benefit. Mannose directly powers immune cells while promoting a more favorable microbial ecosystem.”
This discovery opens several bridging avenues. B.Animals It is already widely consumed as a probiotic with an established safety record and could be an attractive adjunct to existing immunotherapies. Oral intake of mannose is well tolerated in humans and may provide a simpler and more standardized approach than live bacteria. This study also highlights the Hippo-YAP1 pathway as a new therapeutic target to enhance T cell function in cancer. Future clinical studies will be needed to validate these findings in melanoma patients and determine the optimal dosing strategy. If confirmed, this probiotic and metabolite approach could provide a safe, low-cost strategy to overcome resistance to immune checkpoint inhibition and improve outcomes for many patients who currently do not benefit from these treatments.
sauce:
Chinese Academy of Sciences
Reference magazines:
Lee, C. others. (2026). Bifidobacterium animalis suppresses melanoma progression and activates antitumor immunity by inhibiting YAP1 expression in CD8+ T cells. Cancer biology and medicine. DOI: 10.20892/j.issn.2095-3941.2025.0652. https://www.cancerbiomed.org/content/early/2026/05/06/j.issn.2095-3941.2025.0652
