Hepatocellular carcinoma-derived FOXO1 inhibits tumor progression by suppressing IL-6 secretion from macrophages

Tumor heterogeneity dominates tumor biological behavior and shapes the tumor microenvironment. However, the mechanisms of tumor genetic features modulate immunity response were not clearly clarified. Tumor associated macrophages (TAMs) exert distinct immune functions in the progression of hepatocellular carcinoma (HCC) based on the inducible phenotype. FOXO family members sense changes in the extracellular or intracellular environment by activating a series of signaling pathways. FOXO1, a transcription factor that a common suppressor in hepatocellular carcinoma, correlated with a better tumor biological behavior in HCC through shaping macrophages anti-tumour response. Here, we found that human HCC tissue microarray (TMA) slides were employed to showed tumor derived FOXO1 negatively related with distribution of protumour macrophages. This phenomenon was confirmed in mouse xenograft model and in vitro. HCC-derived FOXO1 inhibits tumorigenesis not only by targeting tumor cells but also by synchronizing with re-educated macrophages. These effects may be partially dependent on FOXO1 transcriptionally modulates IRF-1/nitrio oxide (NO) axis in exerting effects in macrophages and decreasing IL-6 releasing from macrophages in tumor microenvironment indirectly. This feedback suppressed the progression of HCC by inactivation of IL-6/STAT3 in HCC. It implicates the potential role of FOXO1 in the therapeutic effects for modulating immune response by targeting macrophages.