Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
Acc Chem Res. 2020 Dec 15;53(12):2765-2776. doi: 10.1021/acs.accounts.0c00518. Epub 2020 Nov 8.
Therapeutic manipulation of the immune system against cancer has revolutionized the treatment of several advanced-stage tumors. While many have benefited from these treatments, the proportion of patients responding to immunotherapies is still low. Nanomedicines have promise to revolutionize tumor treatments through spatiotemporal control of drug activity. Such control of drug function could allow enhanced therapeutic actions of immunotherapies and reduced side effects. However, only a handful of formulations have been able to reach human clinical studies so far, and even fewer systems are being used in the clinic. Among translatable formulations, self-assembled nanomedicines have shown unique and versatile features for dealing with the heterogeneity and malignancy of tumors in the clinic. Such nanomedicines can be designed to promote antitumor immune responses through a series of immunopotentiating functions after being directly injected into tumors, or achieving selective tumor accumulation upon intravenous administration. Thus, tumor-targeted nanomedicines can enhance antitumor immunity by several mechanisms, such as inducing immunogenic damage to cancer cells, altering the tumor immune microenvironment by delivering immunomodulators, or eliminating or reprogramming immunosuppressive cells, enhancing the exposure of tumor-associated antigens to antigen presenting cells, stimulating innate immunity mechanisms, and facilitating the infiltration of antitumor immune cells and their interaction with cancer cells. Moreover, nanomedicines can be engineered to sense intratumoral stimuli for activating specific immune responses or installed with ligands for increasing drug levels in tumors, granting subcellular delivery, and triggering immune signals and proliferation of immune cells. Thus, the ability of nanomedicines to exert immunomodulatory functions selectively in tumor and tumor-associated tissues, such as draining lymph nodes, increases the efficiency of the treatments, while avoiding systemic immunosuppressive toxicities and the exacerbation of adverse immune responses. Moreover, the compartmentalized structure of self-assembled nanomedicines offers the possibility to coload a variety of drugs for controlled pharmacokinetics, enhanced tumor delivery, and synergistic therapeutic output. Also, by integrating imaging functionalities into nanomedicines, it is possible to develop theranostic platforms reporting the immune settings of tumors as well as the effects of nanomedicines on the tumor immune microenvironment. Herein, we critically reviewed significant strategies for developing nanomedicines capable of potentiating antitumor immune responses by surmounting biological barriers and modulating antitumor immune signals. Moreover, the potential of these nanomedicines for developing innovative anticancer treatments by targeting particular cells is discussed. Finally, we present our perspectives on the awaiting challenges and future directions of nanomedicines in the age of immunotherapy.
治疗性免疫疗法在癌症治疗方面的突破,已经改变了多种晚期肿瘤的治疗方式。虽然许多患者从这些治疗中受益,但免疫疗法的响应比例仍然较低。纳米医学有望通过药物活性的时空控制来彻底改变肿瘤治疗。这种药物功能的控制可以增强免疫疗法的治疗作用,减少副作用。然而,到目前为止,只有少数制剂能够进入人体临床研究,在临床上使用的系统则更少。在可转化的制剂中,自组装纳米药物在处理临床肿瘤的异质性和恶性方面显示出独特和多功能的特性。这些纳米药物可以通过一系列免疫增强功能直接注射到肿瘤中,或在静脉给药后实现选择性肿瘤积累,从而促进抗肿瘤免疫反应。因此,肿瘤靶向纳米药物可以通过多种机制增强抗肿瘤免疫,例如诱导癌细胞产生免疫原性损伤,通过递送免疫调节剂改变肿瘤免疫微环境,或消除或重新编程免疫抑制细胞,增强肿瘤相关抗原与抗原呈递细胞的暴露,刺激固有免疫机制,并促进抗肿瘤免疫细胞的浸润及其与癌细胞的相互作用。此外,纳米药物可以被设计为感应肿瘤内的刺激物,以激活特定的免疫反应,或者安装配体以增加肿瘤中的药物水平,实现亚细胞递送,并触发免疫信号和免疫细胞的增殖。因此,纳米药物在肿瘤和肿瘤相关组织(如引流淋巴结)中选择性发挥免疫调节功能的能力提高了治疗效率,同时避免了全身免疫抑制毒性和不良反应免疫反应的加剧。此外,自组装纳米药物的分隔结构为控制药物动力学、增强肿瘤递药和协同治疗输出提供了同时加载多种药物的可能性。此外,通过将成像功能集成到纳米药物中,有可能开发出报告肿瘤免疫状态以及纳米药物对肿瘤免疫微环境影响的治疗诊断平台。在此,我们批判性地综述了通过克服生物学障碍和调节抗肿瘤免疫信号来增强抗肿瘤免疫反应的纳米药物的重要发展策略。此外,还讨论了这些纳米药物通过靶向特定细胞开发创新抗癌治疗的潜力。最后,我们提出了我们对纳米医学在免疫治疗时代面临的挑战和未来方向的看法。