Fusobacterium nucleatum in colorectal cancer: Ally mechanism and targeted therapy strategies

In recent years, the regulatory role of the gut microbiota in the initiation and progression of colorectal cancer (CRC) has attracted growing attention. Among the key microbial contributors, Fusobacterium nucleatum (Fn) has been identified as a critical pathogenic factor in CRC. As an oral anaerobic commensal, Fn is rarely found in the lower gastrointestinal tract of healthy individuals. However, under pathological conditions, it can ectopically colonize the gastrointestinal tract. Once enriched in the colorectal environment, mounting evidence suggests that Fn is involved in multiple aspects of CRC pathogenesis, including initiation, progression, metastasis, and resistance to conventional therapies such as chemotherapy, radiotherapy, and immunotherapy. A recent review by Wei Wei and Diwei Zheng's team at the Institute of Process Engineering systematically outlines the pathogenic mechanisms of Fn in CRC and summarizes both current and emerging strategies for its therapeutic targeting. Furthermore, the authors propose potential approaches to overcome existing challenges in Fn modulation, aiming to facilitate more effective therapeutic interventions and improve clinical outcomes.

Focusing on the dual themes of "pathogenic mechanisms and therapeutic strategies," this review first details the multifaceted roles of Fn in CRC progression. It explores how Fn contributes to disease through processes such as microbial colonization, activation of oncogenic signaling pathways, and modulation of the immune microenvironment. Key virulence factors—such as FadA, Fap2, and RadD—are highlighted for their roles in tumor development and resistance to treatment. Given its tumor-promoting effects, eliminating Fn is considered a promising strategy for improving CRC outcomes. The review systematically discusses various therapeutic approaches targeting Fn, including small-molecule inhibitors (such as antibiotics and natural extracts), nanomedicines (such as inorganic nanoparticles and organic polymers) and biopharmaceuticals (such as antimicrobial peptides and phages). While these approaches have demonstrated potential in preclinical studies, they still face major challenges, including limited specificity, systemic toxicity, and disruption of microbial homeostasis.

As our understanding of Fn's pathogenic mechanisms deepens, highly specific and low-toxicity interventions are expected to emerge, driving CRC treatment toward greater precision, efficiency, and personalization. This review outlines several promising future directions:

• Subspecies-targeted interventions: The therapeutic targeting of Fn subspecies remains underexplored. Future strategies may focus on dominant strains such as Fna and their specific virulence factors to enable personalized treatment.
• Intracellular clearance: Since Fn can survive and replicate within tumor and immune cells, the development of strategies capable of eliminating intracellular Fn is crucial to overcoming its immune evasion and persistence.
• Vaccine development: Vaccines represent a powerful tool for specific immune protection. Targeting Fn-specific virulence factors or host-interacting receptors could enable precise clearance. However, future work must address the optimization of antigen selection and adjuvant combinations to enhance immunogenicity and efficacy.

Collectively, these emerging strategies hold the potential to overcome current limitations and serve as valuable references for developing microbe-targeted therapies in CRC and other microbiota-associated cancers.

Sources: https://spj.science.org/doi/10.34133/research.0640