RNF8 enhances the sensitivity of PD-L1 inhibitor against melanoma through ubiquitination of galectin-3 in stroma.

The failure of melanoma immunotherapy can be mediated by immunosuppression in the tumor microenvironment (TME), and insufficient activation of effector T cells against the tumor. Here, we show that inhibition of galectin-3 (gal-3) enhances the infiltration of T cells in TME and improves the sensitivity of anti-PD-L1 therapy. We identify that RNF8 downregulated the expression of gal-3 by K48-polyubiquitination and promoted gal-3 degradation via the ubiquitin-proteasome system. RNF8 deficiency in the host but sufficiency in implanted melanoma results in immune exclusion and tumor progression due to the upregulation of gal-3. Upregulation of gal-3 decreased the immune cell infiltration by restricting IL-12 and IFN-γ. Inhibition of gal-3 reverses immunosuppression and induces immune cell infiltration in the tumor microenvironment. Moreover, gal-3 inhibitor treatment can increase the sensitivity of PD-L1 inhibitors via increasing immune cell infiltration and enhancing immune response in tumors. This study reveals a previously unrecognized immunoregulation function of RNF8 and provides a promising strategy for the therapy of "cold" tumors. Tremendous effects of melanoma treatment can be achieved by facilitating immune cell infiltration combined with anti-PD-L1 treatment.

Accumulation of polystyrene microplastics induces liver fibrosis by activating cGAS/STING pathway.

The environmental pollution from microplastics has caused concern from the whole society due to its harm to organisms. However, the effect of microplastics on liver damage and fibrosis remains unclear in the case of long-term accumulation. The present study demonstrated that the 0.1 µm microplastic could enter hepatocytes from circulation and result liver damage even at a low concentration. Microplastic exposure could induce DNA damage in both nucleus and mitochondria, by which the dsDNA fragment was translocated into cytoplasm and triggered the DNA sensing adaptor STING. The activation of cGAS/STING pathway initiated the downstream cascade reaction, the NFκB translocated into nucleus and upregulated pro-inflammatory cytokines expression, and thus facilitating liver fibrosis eventually. Furthermore, inhibition of STING could alleviate the liver fibrosis via blocking the NFκB translocation and fibronectin expression. This study provided a valuable insight to elucidate the potential risk and mechanism of hepatic toxicity and fibrosis induced by microplastics.