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

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 phi) 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 phi polarization as well as its effect on CRC malignancy. Fn infection facilitated differentiation of M phi into the M2-like M phi phenotype by in vitro study. Histological observation from Fn-positive CRC tissues confirmed the abundance of tumor-infiltrating M2-like M phi. Fn-induced M2-like M phi polarization was weakened once inhibiting a highly expressed damage-associated molecular pattern (DAMP) molecule S100A9 mainly derived from Fn-challenged M phi and CRC cells. In addition, Fn-challenged M2-like M phi 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-kappa B signaling pathway mediated Fn-induced S100A9 expression and subsequent M2-like M phi activation. Collectively, these findings indicate that elevated S100A9 in Fn-infected CRC microenvironment participates in M2-like M phi polarization, thereby facilitating CRC malignancy. Furthermore, targeting TLR4/NF-kappa B/S100A9 cascade may serve as promising immunotherapeutic strategy for Fn-associated CRC.

Automated summary

The research found that Fusobacterium nucleatum infection is closely associated with the development of colorectal cancer, primarily by promoting the polarization of M2 macrophages to exacerbate tumor malignancy. S100A9 is a key signaling molecule that regulates the activation of M2 macrophages. Targeting the TLR4/NF-kappa B/S100A9 cascade may serve as a promising therapeutic strategy for Fusobacterium nucleatum-associated colorectal cancer.