FBXW11 regulates macrophage polarization and enhances the anti-tumor activity

Macrophages can be polarized to various states in physiologic and pathologic microenvironments. The simplified but widely accepted M1/M2 polarization states play contradictory roles in tumor progression. The ubiquitin-proteasome system (UPS), particularly F-box proteins, has been reported to be involved in immune regulation. However, the role of F-box and WD-40 domain protein 11 (FBXW11) on macrophage remains unclear. Here, the effects of FBXW11 on macrophage polarization and anti-tumor function were investigated. The results showed that FBXW11 promoted macrophage proliferation and induced a mild M1 polarization phenotype in the absence of tumor cells. Furthermore, overexpression of Fbxw11 enhanced the M1 polarization of macrophages in tumor co-culture system. Moreover, overexpression of Fbxw11 also enhanced glucose uptake and increased mitochondrial reactive oxygen species (ROS) levels, while reducing the mitochondrial membrane potential (Δψ_m) in macrophages in tumor co-culture system. Functionally, Fbxw11 overexpression increased the phagocytosis and killing of A20 lymphoma cells. RNA-sequencing analysis revealed that FBXW11 activated critical innate immune pathways, including JAK-STAT, NF-κB, and Toll-like receptor signaling, and upregulated effector molecules such as IL-6 and type I interferons. Collectively, our results reveal that FBXW11 paly a positive role on macrophage M1 polarization and anti-tumor function, which broaden the knowledge about how UPS modulates innate immunity.