State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203, China.
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Adv Mater. 2019 Apr;31(14):e1805888. doi: 10.1002/adma.201805888. Epub 2019 Feb 14.
Chemoimmunotherapy is reported to activate a robust T cell antitumor immune response by triggering immunogenic cell death (ICD), which has initiated a number of clinical trials. However, current chemoimmunotherapy is restricted to a small fraction of patients due to low drug delivery efficacy and immunosuppression within the tumor microenvironment. A tumor microenvironment-activatable prodrug vesicle for cancer chemoimmunotherapy using ICD is herein reported. The prodrug vesicles are engineered by integrating an oxaliplatin (OXA) prodrug and PEGylated photosensitizer (PS) into a single nanoplatform, which show tumor-specific accumulation, activation, and deep penetration in response to the tumoral acidic and enzymatic microenvironment. It is demonstrated that codelivery of OXA prodrug and PS can trigger ICD of the tumor cells by immunogenic cells killing. The combination of prodrug vesicle-induced ICD with Î ± CD47-mediated CD47 blockade further facilitates dendritic cell (DC) maturation, promotes antigen presentation by DCs, and eventually propagates the antitumor immunity of ICD. CD47 blockade and ICD induction efficiently inhibit the growth of both primary and abscopal tumors, suppress tumor metastasis, and prevent tumor recurrence. Collectively, these results imply that boosting antitumor immunity using ICD induction and suppressing tumor immune evasion via CD47 blockade might be promising for improved cancer chemoimmunotherapy.
化免疫疗法通过触发免疫原性细胞死亡（ICD）来激活强大的抗肿瘤 T 细胞免疫反应，这引发了许多临床试验。然而，由于肿瘤微环境内药物输送效率低和免疫抑制，目前的化免疫疗法仅限于一小部分患者。本文报道了一种用于癌症化免疫治疗的基于 ICD 的肿瘤微环境激活前药囊泡。前药囊泡通过将奥沙利铂（OXA）前药和聚乙二醇化光敏剂（PS）整合到单个纳米平台中进行工程设计，该平台能够响应肿瘤酸性和酶促微环境特异性地积累、激活和深入渗透。结果表明，OXA 前药和 PS 的共递送可以通过免疫原性细胞杀伤触发肿瘤细胞的 ICD。前药囊泡诱导的 ICD 与 Î ± CD47 介导的 CD47 阻断相结合，进一步促进树突状细胞（DC）成熟，促进 DC 呈递抗原，并最终传播 ICD 的抗肿瘤免疫。CD47 阻断和 ICD 诱导可有效抑制原发性和远隔肿瘤的生长，抑制肿瘤转移，并防止肿瘤复发。总的来说，这些结果表明，使用 ICD 诱导增强抗肿瘤免疫并通过 CD47 阻断抑制肿瘤免疫逃逸可能是改善癌症化免疫治疗的有前途的方法。
