Abstract C037: Fructose-induced Akkermansia muciniphila promotes colorectal cancer progression through N-acetylneuraminic acid-mediated macrophage reprogramming

Purpose: High-fructose consumption is epidemiologically linked to increased colorectal cancer (CRC) risk, yet the mechanistic connections between fructose-induced microbial alterations and immune suppression remain unclear. Previous studies have shown that fructose intake can increase Akkermansia muciniphila levels. This study investigated how fructose exposure promotes CRC progression through A. muciniphila and whether therapeutic targeting is possible while preserving A. muciniphila's metabolic benefits. Methods: The impact of long-term oral A. muciniphila administration was assessed using AOM-DSS spontaneous CRC mouse model. Macrophage phenotypes were characterized by flow cytometry and RNA sequencing of bone marrow-derived macrophages (BMDMs). Published metabolomics datasets were reanalyzed to identify intestinal lumen metabolites associated with A. muciniphila colonization. The functional relevance of candidate metabolites was examined through ex vivo BMDM treatment followed by adoptive transfer into MC38 tumor-bearing mice. Results: Oral A. muciniphila administration enhanced tumor growth in AOM-DSS CRC model, accompanied by increased colonic macrophage infiltration and altered polarization characterized by reduced CD206 expression. Dataset reanalysis revealed elevated N-acetylneuraminic acid (Neu5Ac), a metabolite released during A. muciniphila-mediated mucin degradation, in the ileum following A. muciniphila administration. Neu5Ac treatment reprogrammed macrophages toward a tumor-promoting phenotype with enhanced immunosuppressive and pro-tumorigenic signaling. Adoptive transfer of Neu5Ac-treated macrophages accelerated MC38 tumor progression in vivo. Conclusions: These findings identify a novel fructose–A. muciniphila–Neu5Ac–macrophage immunometabolic axis linking dietary fructose to immune dysfunction in CRC. High fructose consumption enriches A. muciniphila, which releases Neu5Ac into the intestinal lumen, subsequently reprogramming macrophages toward a tumor-promoting phenotype that accelerates CRC progression. This work identifies a potential therapeutic target for diet-associated CRC while preserving the metabolic benefits of A. muciniphila. Citation Format: Yingzhao Wang, Marcus Goncalves. Fructose-induced Akkermansia muciniphila promotes colorectal cancer progression through N-acetylneuraminic acid-mediated macrophage reprogramming [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr C037.