Wang Xiaoqing, Lu Xing, Liu Chang, Cheng Hao, Tan Xiangshi
Department of Chemistry, Fudan University, Shanghai 200433, China.
Int J Mol Sci. 2025 Sep 5;26(17):8649. doi: 10.3390/ijms26178649.
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.
低免疫原性和免疫逃逸是肝细胞癌（HCC）有效免疫治疗的瓶颈。我们通过将STING激动剂cGAMP包裹在脂质体中，并将抗PD-L1纳米抗体偶联到脂质体表面，制备并表征了一种双靶点脂质体复合物XA5508。使用原位HCC小鼠模型研究了XA5508的抗肿瘤作用和药理机制。XA5508能够有效抑制原位HCC，具有肿瘤靶向递送和STING激动剂cGAMP缓释的特点。药理机制研究表明，XA5508激活STING信号通路，增加CD8 T细胞的细胞毒性，逆转以M2型巨噬细胞为代表的免疫抑制性肿瘤微环境（TME），并将冷肿瘤转变为热肿瘤。另一方面，cGAMP诱导HCC中PD-L1表达上调，增强抗PD-L1纳米抗体（Nb）的反应并逃避免疫检查点PD-1/PD-L1的阻断。XA5508对HCC显示出STING激动剂和抗PD-L1纳米抗体显著的抗肿瘤作用，为开发HCC新药提供了创新策略。
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