Abstract：
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.
摘要：
表阿霉素（EPI）单独可以在残留的肿瘤细胞中引发轻度保护性自噬，导致免疫抑制的微环境。这会加速残留肿瘤的复发，并导致抗程序性死亡配体1（抗PD-1）/PD-L1治疗耐药，在肿瘤免疫治疗中构成了重大的临床挑战。针对PD-1/PD-L1通路的检查点抑制剂和扩增自噬的组合为肿瘤治疗提供了一种创新的方法，可以防止肿瘤免疫逃逸，增强治疗识别。在这里，我们的目的是合成一种氧化还原触发的自噬诱导的纳米平台，具有SA和EA诱导的PD-L1抑制作用。透明质酸（HA）骨架和精氨酸段促进活性纳米平台靶向，细胞摄取，和渗透。PLGLAG肽通过在肿瘤微环境中过度表达基质金属蛋白酶-2(MMP-2)而被切割,PD-L1抑制剂D-PPA释放抑制肿瘤免疫逃逸。强烈的自噬诱导剂，STF-62247和EPI，由于受肿瘤细胞中高谷胱甘肽（GSH）浓度影响的二硫键裂解而释放。EPI和STF联合诱导细胞凋亡和自噬性死亡，有效消除大部分肿瘤细胞。这表明SA&EA纳米平台具有比单个STF@AHMPP和EPI@AHMPTP组更好的治疗功效。这项研究提供了一种建立氧化还原触发的自噬诱导的具有PD-L1抑制的纳米平台以增强化学免疫疗法的方法。
