通过PD-L1阻断和表观遗传重编程用于协同癌症免疫疗法的模块化工程外膜囊泡
Modular engineered outer membrane vesicles for synergistic cancer immunotherapy via PD-L1 blockade and epigenetic reprogramming.
摘要(中文译文)
免疫检查点抑制剂显著改善了晚期黑色素瘤的治疗效果，然而其临床疗效在很大程度上受到低总体缓解率以及原发性或获得性耐药的限制。在此，我们开发了一种经SpyCatcher工程化改造的细菌外膜囊泡（OMV）平台，用于共同递送PD-1/PD-L1抑制剂D-PPA1肽和表观遗传调节剂泽布拉林（Zeb）。所构建的共同递送系统OMV@PPA/Zeb有效阻断了PD-1/PD-L1相互作用，并显著上调了黑色素瘤细胞中的黑色素瘤相关抗原，包括CD146和TRP1。在皮下黑色素瘤小鼠模型中，OMV@PPA/Zeb大幅抑制了肿瘤生长，且未出现明显的全身毒性。此外，OMV@PPA/Zeb显著促进了CD8 T细胞的浸润与活化，同时减少了肿瘤微环境中的调节性T细胞（Tregs）。该平台所激发的强效抗肿瘤免疫应答有助于增强其抗黑色素瘤的治疗疗效。总体而言，本研究提供了一种基于OMV的模块化策略，用于晚期肿瘤的联合免疫治疗。
Abstract
Immune checkpoint inhibitors have significantly improved therapeutic outcomes in advanced melanoma; however, their clinical efficacy is greatly limited by low overall response rates and the primary or acquired resistance. Here, we developed a SpyCatcher-engineered bacterial outer membrane vesicle (OMV) platform for the co-delivery of a PD-1/PD-L1 inhibitor, the D-PPA1 peptide, and the epigenetic regulator zebularine (Zeb). The resulting co-delivery system, OMV@PPA/Zeb, effectively blocked PD-1/PD-L1 interactions and markedly upregulated melanoma-associated antigens, including CD146 and TRP1, in melanoma cells. In a subcutaneous melanoma mouse model, OMV@PPA/Zeb substantially suppressed tumor growth without noticeable systemic toxicity. Moreover, OMV@PPA/Zeb significantly promoted the infiltration and activation of CD8 T cells while reducing regulatory T cells (Tregs) within the tumor microenvironment. The potent antitumor immune response elicited by this platform contributed to its enhanced therapeutic efficacy against melanoma. Overall, this study provides a modular OMV-based strategy for combination immunotherapy in advanced tumors.
如何引用
AMA
Longxue Guan, Qinxiao Sun, Dandan Liang, Zhimin Li, Shiqi Zhang, Laili Huang, et al. Modular engineered outer membrane vesicles for synergistic cancer immunotherapy via PD-L1 blockade and epigenetic reprogramming.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1915499.
APA
Longxue Guan, Qinxiao Sun, Dandan Liang, Zhimin Li, Shiqi Zhang, Laili Huang, et al (2026). Modular engineered outer membrane vesicles for synergistic cancer immunotherapy via PD-L1 blockade and epigenetic reprogramming.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1915499
GB/T 7714
Longxue Guan, Qinxiao Sun, Dandan Liang, Zhimin Li, Shiqi Zhang, Laili Huang, et al. Modular engineered outer membrane vesicles for synergistic cancer immunotherapy via PD-L1 blockade and epigenetic reprogramming.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1915499.
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