Fusobacterium nucleatum, a key oral-pathobiont in colorectal cancer (CRC), has evolved from a presumed “passenger” to an active “co-conspirator” in tumorigenesis. This review systematically delineates its core role as an “architect of the immune microenvironment,” whereby it remodels T-cell immune responses through precise mechanisms to establish an immunosuppressive tumor microenvironment. Specifically, F. nucleatum employs virulence factors such as Fap2 and FadA for specific colonization, and achieves immune evasion by inhibiting NK and T-cell function and recruiting myeloid-derived suppressor cells (MDSCs). Post-colonization, it further fine-tunes T-cell subsets: driving Th17 polarization to create a pro-inflammatory milieu while suppressing the infiltration and function of CD8 + T cells and promoting their exhaustion. Intriguingly, it upregulates programmed death-ligand 1 (PD-L1) expression, which may conversely enhance tumor sensitivity to anti-PD-1/PD-L1 immunotherapy. Moreover, it collaborates with other microbes via quorum sensing and the oral-gut axis to construct a procarcinogenic ecosystem. Based on these mechanisms, F. nucleatum exhibits substantial clinical translational potential. Its load serves as an effective non-invasive diagnostic biomarker and a prognostic predictor, and may help predict responses to immune checkpoint inhibitors. Therapeutically, strategies targeting the eradication or inhibition of F. nucleatum —including antibiotics, specific phages, virulence factor inhibitors, and combination immunotherapy—represent highly promising novel directions. Despite existing challenges, future efforts to deepen mechanistic understanding, develop precision intervention tools, and establish integrated patient stratification systems hold the potential to revolutionize CRC prevention, diagnosis, and combination therapy by targeting F. nucleatum .
Wuyi et al. (Wed,) studied this question.