Frontiers Science Center for Cell Responses, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, and College of Life Sciences, Nankai University, Tianjin, 300071, China.
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
Adv Mater. 2022 Aug;34(31):e2203309. doi: 10.1002/adma.202203309. Epub 2022 Jul 5.
Immunotherapy has received tremendous attention for tumor treatment, but the efficacy is greatly hindered by insufficient tumor-infiltration of immune cells and immunosuppressive tumor microenvironment. The strategy that can efficiently activate cytotoxic T lymphocytes and inhibit negative immune regulators will greatly amplify immunotherapy outcome, which is however very rare. Herein, a new kind of semiconducting polymer (SP) nanoparticles is developed, featured with surface-mimicking protein secondary structure (SPSS NPs) for self-synergistic cancer immunotherapy by combining immunogenic cell death (ICD) and immune checkpoint blockade therapy. The SPs with excellent photodynamic property are synthesized by rational fluorination, which can massively induce ICD. Additionally, the peptide antagonists are introduced and self-assembled into β-sheet protein secondary structures on the photodynamic NP surface via preparation process optimization, which function as efficient lysosome-targeting chimaeras (LYTACs) to mediate the degradation of programmed cell death ligand-1 (PD-L1) in lysosome. In vivo experiments demonstrate that SPSS NPs can not only elicit strong antitumor immunity to suppress both primary tumor and distant tumor, but also evoke long-term immunological memory against tumor rechallenge. This work introduces a new kind of robust immunotherapy agents by combining well-designed photosensitizer-based ICD induction and protein secondary structures-mediated LYTAC-like multivalence PD-L1 blockade, rendering great promise for synergistic immunotherapy.
免疫疗法在肿瘤治疗方面受到了极大的关注，但由于免疫细胞在肿瘤中的浸润不足和免疫抑制性肿瘤微环境的存在，其疗效受到了极大的阻碍。能够有效激活细胞毒性 T 淋巴细胞并抑制负性免疫调节因子的策略将极大地放大免疫治疗的效果，但这种策略非常少见。在此，开发了一种新型半导体聚合物（SP）纳米颗粒，其具有表面模拟蛋白二级结构（SPSS NPs），通过结合免疫原性细胞死亡（ICD）和免疫检查点阻断治疗，实现了自我协同的癌症免疫治疗。通过合理的氟化作用合成了具有优异光动力特性的 SP，可大量诱导 ICD。此外，通过制备工艺优化，将肽拮抗剂引入并自组装到光动力 NP 表面的β-折叠蛋白二级结构上，作为有效的溶酶体靶向嵌合体（LYTAC），介导溶酶体中程序性细胞死亡配体 1（PD-L1）的降解。体内实验表明，SPSS NPs 不仅能引发强烈的抗肿瘤免疫，抑制原发肿瘤和远处肿瘤，还能引发针对肿瘤再挑战的长期免疫记忆。这项工作通过结合精心设计的基于光敏剂的 ICD 诱导和蛋白二级结构介导的 LYTAC 样多价 PD-L1 阻断，引入了一种新型的强大免疫治疗剂，为协同免疫治疗提供了巨大的前景。
