Lu Shijia, Zhang Chenxiao, Wu Huiru, Wang Junjie, Wang Jinglong, Zhao Limei, Ren Tianyang, Li Guofei
Shengjing Hospital of China Medical University, Department of Pharmacy, No. 36, Sanhao Street, Shenyang, 110004, China.
Mater Today Bio. 2025 May 8;32:101801. doi: 10.1016/j.mtbio.2025.101801. eCollection 2025 Jun.
Liver cancer is one of the malignant tumors with high morbidity and mortality worldwide and lacks effective clinical treatments. CD8 T cell-based immunotherapy is the most promising option for the treatment of liver cancer, but its application is severely limited by low infiltration and functional exhaustion of CD8 T cells in liver cancer tissues. To overcome this problem, in this study, pH/matrix metalloproteinase-9 (MMP-9) dual-responsive liposomes were constructed and co-loaded with a galectin-3 (Gal-3) inhibitor, GB1107, a programmed death receptor 1 (PD-1) inhibitor, BMS1166, and an androgen receptor (AR) antagonist, enzalutamide, for immunotherapy studies in liver cancer. Specifically, the co-loaded liposomes (GBE@LP) were produced with a one-two punch targeting antitumor immunity. First, GBE@LP exhibited prolonged circulation in the blood and accumulated in liver cancer tissues through the enhanced permeability and retention effect due to the presence of surface polyethylene glycol. After entering liver cancer tissues, GBE@LP responded to the low pH and overexpression of MMP-9 in the microenvironment to promote the release of GB1107, BMS1166, and enzalutamide, thus, realizing the intelligent release of drugs targeting liver cancer. Upon reaching liver tumor tissues, GB1107 can inhibit overexpressed Gal-3 to transform liver cancer from a "cold" to a "hot" tumor and enable deep penetration by CD8 T cells. In addition, BMS1166 and enzalutamide inhibit PD-1 and AR in CD8 T cells, reversing CD8 T cell exhaustion and enhancing their killing activity. In vivo and in vitro experiments confirmed the significant antitumor effects of GBE@LP in liver cancer. These results indicate that our strategy is expected to reverse the "cold" tumor and immune exhaustion state of liver cancer, which not only improves therapeutic efficacy, but also provides a new paradigm for the exploration of liver cancer immunotherapy.
肝癌是全球发病率和死亡率都很高的恶性肿瘤之一，且缺乏有效的临床治疗方法。基于CD8 T细胞的免疫疗法是治疗肝癌最有前景的选择，但其应用受到肝癌组织中CD8 T细胞低浸润和功能耗竭的严重限制。为克服这一问题，本研究构建了pH/基质金属蛋白酶-9（MMP-9）双响应脂质体，并将半乳糖凝集素-3（Gal-3）抑制剂GB1107、程序性死亡受体1（PD-1）抑制剂BMS1166和雄激素受体（AR）拮抗剂恩杂鲁胺共同载入其中，用于肝癌的免疫治疗研究。具体而言，共同载入的脂质体（GBE@LP）通过双重靶向抗肿瘤免疫发挥作用。首先，GBE@LP在血液中循环时间延长，并由于表面聚乙二醇的存在通过增强的渗透和滞留效应在肝癌组织中蓄积。进入肝癌组织后，GBE@LP对微环境中的低pH值和MMP-9的过表达做出响应以促进GB1107、BMS1166和恩杂鲁胺的释放，从而实现对肝癌的靶向药物智能释放。到达肝肿瘤组织后，GB1107可抑制过表达的Gal-3，将肝癌从“冷”肿瘤转变为“热”肿瘤，并使CD8 T细胞能够深入浸润。此外，BMS1166和恩杂鲁胺抑制CD8 T细胞中的PD-1和AR，逆转CD8 T细胞耗竭并增强其杀伤活性。体内和体外实验证实了GBE@LP在肝癌中的显著抗肿瘤作用。这些结果表明，我们的策略有望逆转肝癌的“冷”肿瘤和免疫耗竭状态，这不仅提高了治疗效果，还为肝癌免疫治疗的探索提供了新的范例。
