Abstract
The low immunogenicity and immune escape are bottlenecks for effective hepatocellular carcinoma (HCC) immunotherapy. We prepared and characterized a dual-target liposome complex, XA5508, by encapsulating the STING agonist cGAMP in liposomes and conjugating an anti-PD-L1 nanobody to the liposome surface. The anti-tumor effect and pharmacological mechanism of XA5508 were investigated using an in situ HCC mouse model. XA5508 can effectively inhibit in situ HCC with the characteristics of tumor-targeted delivery and sustained release of STING agonist cGAMP. The pharmacological mechanism study indicates that XA5508 activates the STING signaling pathway, increases the cytotoxicity of CD8(+) T cells, reverses the immunosuppressive tumor microenvironment (TME) represented by M2-type macrophages, and transforms cold tumors into hot tumors. On the other hand, cGAMP induces the upregulation of PD-L1 expression in HCC, enhances the response of anti-PD-L1 nanobody (Nb) and the escape blockade of immune checkpoint PD-1/PD-L1. XA5508 shows remarkable anti-tumor effects of STING agonist and anti-PD-L1 nanobody against HCC, providing an innovative strategy for the development of new drugs for HCC.