Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) Bethesda, Maryland 20892, United States.
Acc Chem Res. 2020 Oct 20;53(10):2044-2054. doi: 10.1021/acs.accounts.0c00334. Epub 2020 Sep 2.
Immunotherapy has attracted significant interest because of its tremendous potential in cancer therapy. The recent advances in the identification of cancer-associated neoantigens, chimeric antigen receptor (CAR) T-cell and immune checkpoint blockade (ICB), have revolutionized the field of cancer immunotherapy. Cancer immunotherapeutic agents typically exhibit strong immune activation or inhibition activity, thereby inducing robust biological effect even when administered at a small dosage. However, in most cases, cancer immunotherapeutic targets are not cancer specific. Some of them are also expressed in nonmalignant normal tissues and the undesired release of the cancer immunotherapeutic agents into these normal tissues may lead to severe side effects. Thus, the on-demand release of the cancer immunotherapeutic agents into the target site is critical to achieving efficient antitumor immune responses while minimizing the side effects.In this Account, we introduce the recent progress of our group and others on the development of stimuli-responsive platforms for cancer immunotherapy. Stimuli-responsive platforms have been constructed for on-demand release of payloads in a temporally and spatially controllable manner. First, we give a brief introduction to the endogenous and exogenous stimuli that are employed to trigger the release of cancer immunotherapeutic agents. The chemical design strategies to construct the specific stimuli-responsive delivery systems are highlighted. Moreover, the recently developed representative stimuli-responsive platforms for the delivery of immune checkpoint inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, stimulator of interferon genes (STING) agonists, and near-infrared photoimmunotherapy (NIR-PIT) agents are discussed in detail. Meanwhile, we summarize the general chemical design for constructing stimuli-responsive delivery platforms targeting immune targets at distinct locations. Lastly, the probable issues on the clinical translation of these stimuli-responsive platforms for cancer immunotherapy are outlined. Since we are still on the way of exploring the immune system and optimizing the chemical design of biomaterials, we hope the information in this account can provide some valuable references for the development of optimal cancer immunotherapeutics.
免疫疗法因其在癌症治疗方面的巨大潜力而引起了广泛关注。最近在鉴定癌症相关的新生抗原、嵌合抗原受体（CAR）T 细胞和免疫检查点阻断（ICB）方面的进展，彻底改变了癌症免疫治疗领域。癌症免疫治疗药物通常表现出强烈的免疫激活或抑制活性，因此即使以小剂量给药也能产生强大的生物学效应。然而，在大多数情况下，癌症免疫治疗靶点不是癌症特异性的。其中一些也在非恶性正常组织中表达，癌症免疫治疗药物意外释放到这些正常组织中可能导致严重的副作用。因此，将癌症免疫治疗药物按需释放到靶位对于实现有效的抗肿瘤免疫反应同时最小化副作用至关重要。
在本述评中，我们介绍了我们小组和其他小组在开发用于癌症免疫治疗的刺激响应平台方面的最新进展。已经构建了刺激响应平台，以在时间和空间上可控的方式按需释放有效载荷。首先，我们简要介绍了用于触发癌症免疫治疗药物释放的内源性和外源性刺激物。突出强调了构建特定刺激响应递药系统的化学设计策略。此外，详细讨论了最近开发的用于递送免疫检查点抑制剂、吲哚胺 2,3-双加氧酶（IDO）抑制剂、干扰素基因刺激物（STING）激动剂和近红外光免疫治疗（NIR-PIT）剂的代表性刺激响应平台。同时，我们总结了针对不同部位免疫靶点构建刺激响应递药平台的一般化学设计。最后，概述了这些用于癌症免疫治疗的刺激响应平台在临床转化方面可能存在的问题。由于我们仍在探索免疫系统并优化生物材料的化学设计，我们希望本述评中的信息能为开发最佳癌症免疫疗法提供一些有价值的参考。
