Fusobacterium nucleatum-associated metabolites in disease pathogenesis: from cancer to immunotherapy

Fusobacterium , especially Fusobacterium nucleatum , has emerged as a metabolically active pathobiont that can affect host physiology and disease pathogenesis. Through its ability to produce and regulate various metabolites, Fusobacterium can shape immune response, cellular metabolism, and disease progression. Short-chain fatty acids (SCFAs), being part of Fusobacterium -associated metabolic changes observed during disease, are involved in microbial cross-feeding and can affect neutrophil recruitment and inflammatory signaling through free fatty acid receptors. In the case of colorectal cancer (CRC), Fusobacterium -derived metabolites can impact tumor and immune cell phenotype via a number of mechanisms, including aryl hydrocarbon receptor (AhR) activation via indole derivatives, inflammatory and metabolic signaling via hydrogen sulfide, as well as an increase in Glucose transporter 1 (GLUT1) expression, lactate production, and histone lactylation via formate-related metabolites. Besides, F. nucleatum can reshape tumor-cell metabolism, including cholesterol biosynthesis through miR-130a-3p-mediated inhibition of AMP-activated protein kinase (AMPK) signaling, whereas butyrate has been reported to counteract this metabolic phenotype in experimental CRC models. In addition, F. nucleatum -associated succinate has been shown to suppress cGAS–Interferon beta (IFN-β) signaling, thereby reducing antitumor immune activation, impairing CD8 + T-cell trafficking, and promoting immune escape and resistance to anti-Programmed Cell Death Protein 1 (PD-1) therapy. The present review provides an overview of current understanding of the biological roles of Fusobacterium -derived metabolites, focusing on SCFAs, succinate, indole derivatives, hydrogen sulfide, and formate-related metabolites.