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Fusobacterium nucleatum  ( Fn ) has been considered as a significant contributor in promoting colorectal carcinoma (CRC) development by suppressing host anti-tumor immunity. Recent studies demonstrated that the aggregation of M2 macrophage (M φ ) was involved in CRC progress driven by  Fn  infection. However, the underlying molecular mechanisms are poorly characterized. Here, we investigated the role of  Fn  in M φ  polarization as well as its effect on CRC malignancy.  Fn  infection facilitated differentiation of M φ  into the M2-like M φ  phenotype by  in vitro  study. Histological observation from  Fn -positive CRC tissues confirmed the abundance of tumor-infiltrating M2-like M φ .  Fn -induced M2-like M φ  polarization was weakened once inhibiting a highly expressed damage-associated molecular pattern (DAMP) molecule S100A9 mainly derived from  Fn -challenged M φ  and CRC cells. In addition,  Fn -challenged M2-like M φ  conferred CRC cells a more malignant phenotype, showing stronger proliferation and migration characteristics  in vitro  and significantly enhanced tumor growth  in vivo , all of which were partially inhibited when S100A9 was lost. Mechanistic studies further demonstrated that activation of TLR4/NF- κ B signaling pathway mediated  Fn -induced S100A9 expression and subsequent M2-like M φ  activation. Collectively, these findings indicate that elevated S100A9 in  Fn -infected CRC microenvironment participates in M2-like M φ  polarization, thereby facilitating CRC malignancy. Furthermore, targeting TLR4/NF- κ B/S100A9 cascade may serve as promising immunotherapeutic strategy for  Fn -associated CRC.

Fusobacterium nucleatum Facilitates M2 Macrophage Polarization and Colorectal Carcinoma Progression by Activating TLR4/NF-κB/S100A9 Cascade