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.

中文翻译：

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具有 PD-L1 抑制作用的氧化还原触发自噬诱导纳米平台，用于增强化疗免疫联合治疗


表柔比星（EPI）单独可以触发残留肿瘤细胞的轻度保护性自噬，从而产生免疫抑制微环境。这加速了残留肿瘤的复发，并导致抗程序性死亡配体1（抗PD-1）/PD-L1治疗耐药，对肿瘤免疫治疗提出了重大的临床挑战。针对PD-1/PD-L1通路的检查点抑制剂与放大自噬的结合为肿瘤治疗提供了一种创新方法，可以防止肿瘤免疫逃逸并增强治疗识别。在此，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，并具有 SA&EA 诱导的 PD-L1 抑制作用。透明质酸 (HA) 骨架和精氨酸片段促进活性纳米平台靶向、细胞摄取和渗透。肿瘤微环境中过表达的基质金属蛋白酶2（MMP-2）会裂解PLGLAG肽，并释放PD-L1抑制剂D-PPA来抑制肿瘤免疫逃逸。由于肿瘤细胞中高浓度谷胱甘肽 (GSH) 影响二硫键断裂，强自噬诱导剂 STF-62247 和 EPI 被释放。 EPI和STF的结合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。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 抑制作用的纳米平台的方法，以增强化疗免疫治疗。