SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC

Emerging evidence indicates that cancer cell-derived exosomes contribute to cancer progression through the modulation of tumor microenvironment, but the underlying mechanisms are not fully elucidated. Here, we reported that hepatocellular carcinoma (HCC)-derived exosomes could remodel macrophages by activating NF-kappa B signaling and inducing pro-inflammatory factors, and resulted in M2-polarized tumor-associated macrophages. In addition, the expression of IFN-gamma and TNF-alpha was inhibited, while the expression of inhibitory receptors such as PD-1 and CTLA-4 was upregulated in T cells by HCC-derived exosome educated macrophages. Data also revealed that HCC exosomes were enriched with miR-146a-5p and promoted M2-polarization. Further investigation demonstrated that the transcription factor Sal-like protein-4 (SALL4) was critical for regulating miR-146a-5p in HCC exosomes and M2-polarization. Mechanistically, SALL4 could bind to the promoter of miR-146a-5p, and directly controlled its expression in exosomes. Blocking the SALL4/miR-146a-5p interaction in HCC reduced the expression of inhibitory receptors on T cells, reversed T cell exhaustion, and delayed HCC progression in DEN/CCL4-induced HCC mice. In conclusion, identification of a role of the exosomal SALL4/miR-146a-5p regulatory axis in M2-polarization as well as HCC progression provides potential targets for therapeutic and diagnostic applications in liver cancer.