National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan 610064, China.
ACS Nano. 2024 May 21;18(20):12870-12884. doi: 10.1021/acsnano.4c00227. Epub 2024 May 10.
Epirubicin (EPI) alone can trigger mildly protective autophagy in residual tumor cells, resulting in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and leads to antiprogrammed death ligand 1 (anti-PD-1)/PD-L1 therapy resistance, posing a significant clinical challenge in tumor immunotherapy. The combination of checkpoint inhibitors targeting the PD-1/PD-L1 pathway and amplifying autophagy presents an innovative approach to tumor treatment, which can prevent tumor immune escape and enhance therapeutic recognition. Herein, we aimed to synthesize a redox-triggered autophagy-induced nanoplatform with SA&EA-induced PD-L1 inhibition. The hyaluronic acid (HA) skeleton and arginine segment promoted active nanoplatform targeting, cell uptake, and penetration. The PLGLAG peptide was cleaved by overexpressing matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment, and the PD-L1 inhibitor D-PPA was released to inhibit tumor immune escape. The intense autophagy inducers, STF-62247 and EPI, were released owing to the cleavage of disulfide bonds influenced by the high glutathione (GSH) concentration in tumor cells. The combination of EPI and STF induced apoptosis and autophagic cell death, effectively eliminating a majority of tumor cells. This indicated that the SA&EA nanoplatform has better therapeutic efficacy than the single STF@AHMPP and EPI@AHMPTP groups. This research provided a way to set up a redox-triggered autophagy-induced nanoplatform with PD-L1 inhibition to enhance chemo-immunotherapy.
表阿霉素（EPI）单独作用于残留肿瘤细胞时可引发轻度保护性自噬，从而形成免疫抑制的微环境。这会加速残留肿瘤的复发，并导致抗程序性死亡配体 1（anti-PD-1）/PD-L1 治疗耐药，给肿瘤免疫治疗带来了重大的临床挑战。针对 PD-1/PD-L1 通路的检查点抑制剂与增强自噬的联合为肿瘤治疗提供了一种创新方法，可防止肿瘤免疫逃逸并增强治疗效果。在此，我们旨在合成一种具有 SA&EA 诱导的 PD-L1 抑制作用的氧化还原触发自噬诱导纳米平台。透明质酸（HA）骨架和精氨酸片段促进了主动纳米平台的靶向、细胞摄取和穿透。PLGLAG 肽在肿瘤微环境中过表达基质金属蛋白酶-2（MMP-2）时被切割，PD-L1 抑制剂 D-PPA 被释放以抑制肿瘤免疫逃逸。在肿瘤细胞中高浓度谷胱甘肽（GSH）的影响下，二硫键被切割，强烈的自噬诱导剂 STF-62247 和 EPI 被释放。EPI 和 STF 的联合作用诱导细胞凋亡和自噬性细胞死亡，有效地消除了大部分肿瘤细胞。这表明 SA&EA 纳米平台比单一的 STF@AHMPP 和 EPI@AHMPTP 组具有更好的治疗效果。本研究为构建具有 PD-L1 抑制作用的氧化还原触发自噬诱导纳米平台以增强化疗-免疫治疗提供了一种方法。
