School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China.
State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Adv Mater. 2021 Oct;33(43):e2102668. doi: 10.1002/adma.202102668. Epub 2021 Aug 31.
Immune evasion is the major obstacle for T-cell-based cancer immunotherapy. The insufficient expression of the tumor-rejection antigen causes the intrinsic immune resistance and high expression of programmed death ligand 1 (PD-L1) induced by interferon gamma (IFN-γ), which accounts for the inducible immune resistance. To deal with both the intrinsic and inducible immune resistance of cancer, a multifunctional prodrug nanovesicle is sequentially developed. It is first sorted out that doxycycline (Doxy) efficiently inhibits autophagy of the tumor cells, and increases the surface level of major histocompatibility complex class I (MHC-I). Then, chameleon-inspired prodrug nanovesicles are engineered for tumor-targeted delivery of Doxy. The prodrug nanovesicles integrating a sheddable poly(ethylene glycol) shell and CRGDK ligand are kept stable during blood circulation, while exposing the targeting ligand in the tumor, which significantly inhibits autophagy, elicits MHC-I expression, increases tumor antigen presentation, recruits more tumor-infiltrating T lymphocytes, and suppresses FN-γ-induced intratumoral PD-L1 expression. After a proof of concept for overcoming intrinsic and inducible immune evasion, the prodrug nanovesicles are applied to validate the efficacy of cancer immunotherapy in two tumor-bearing mouse models. This research thus provides a novel targeting strategy for reducing tumor immune resistance and potentiating tumor immunotherapy.
免疫逃逸是基于 T 细胞的癌症免疫疗法的主要障碍。肿瘤排斥抗原的表达不足导致内在免疫抵抗，干扰素 γ（IFN-γ）诱导的程序性死亡配体 1（PD-L1）高表达，这导致了诱导性免疫抵抗。为了解决癌症的内在和诱导性免疫抵抗，顺次开发了一种多功能前药纳米囊泡。首先，发现多西环素（Doxy）有效地抑制肿瘤细胞的自噬作用，并增加主要组织相容性复合体 I 类（MHC-I）的表面水平。然后，受变色龙启发的前药纳米囊泡被设计用于肿瘤靶向递送达西环素。前药纳米囊泡整合了可脱落的聚乙二醇（PEG）壳和 CRGDK 配体，在血液循环中保持稳定，而在肿瘤中暴露靶向配体，这显著抑制自噬，引发 MHC-I 表达，增加肿瘤抗原呈递，招募更多肿瘤浸润性 T 淋巴细胞，并抑制 IFN-γ 诱导的肿瘤内 PD-L1 表达。在证明克服内在和诱导性免疫逃逸的概念后，前药纳米囊泡被应用于验证两种荷瘤小鼠模型中癌症免疫疗法的疗效。因此，这项研究为降低肿瘤免疫抵抗和增强肿瘤免疫疗法提供了一种新的靶向策略。
