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.

中文翻译：

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肿瘤靶向的免疫疗法纳米药物

对癌症免疫系统的治疗性操纵彻底改变了几种晚期肿瘤的治疗方法。尽管许多人从这些治疗中受益，但对免疫疗法有反应的患者比例仍然很低。纳米药物有望通过时空控制药物活性来彻底改变肿瘤治疗方法。这种对药物功能的控制可以允许增强免疫疗法的治疗作用并减少副作用。但是，到目前为止，只有少数几种制剂能够用于人体临床研究，并且在临床中使用的系统甚至更少。在可翻译的制剂中，自组装的纳米药物在临床中显示出独特和通用的功能来应对肿瘤的异质性和恶性肿瘤。可将此类纳米药物设计为在直接注射入肿瘤后通过一系列免疫增强功能来促进抗肿瘤免疫反应，或在静脉内给药后实现选择性肿瘤蓄积。因此，靶向肿瘤的纳米药物可以通过多种机制增强抗肿瘤免疫力，例如诱导对癌细胞的免疫原性损害，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，增强肿瘤相关抗原暴露于抗原呈递。细胞，刺激先天免疫机制，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，可以对纳米药物进行工程改造，以感测肿瘤内刺激以激活特定的免疫反应，或者与配体一起安装以提高肿瘤中的药物水平，授予亚细胞递送，触发免疫信号和免疫细胞增殖。因此，纳米药物选择性地在肿瘤和与肿瘤相关的组织（例如，引流淋巴结）中发挥免疫调节功能的能力提高了治疗的效率，同时避免了全身性免疫抑制毒性和不良免疫反应的加剧。此外，自组装纳米药物的分隔结构提供了共同装载多种药物以控制药代动力学，增强肿瘤递送和协同治疗输出的可能性。而且，通过将成像功能集成到纳米药物中，有可能开发报告肿瘤免疫设置以及纳米药物对肿瘤免疫微环境的影响的治疗学平台。在这里，我们批判性地审查了重要的战略，以开发能够通过克服生物屏障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。此外，讨论了这些纳米药物通过靶向特定细胞来开发创新抗癌治疗的潜力。最后，我们就免疫疗法时代纳米药物面临的挑战和未来方向提出我们的观点。我们严格审查了开发能够克服生物壁垒和调节抗肿瘤免疫信号从而增强抗肿瘤免疫反应能力的纳米药物的重要策略。此外，讨论了这些纳米药物通过靶向特定细胞来开发创新抗癌治疗的潜力。最后，我们就免疫疗法时代纳米药物面临的挑战和未来方向提出我们的观点。我们严格审查了开发能够克服生物壁垒和调节抗肿瘤免疫信号从而增强抗肿瘤免疫反应能力的纳米药物的重要策略。此外，讨论了这些纳米药物通过靶向特定细胞来开发创新抗癌治疗的潜力。最后，我们就免疫疗法时代纳米药物面临的挑战和未来方向提出我们的观点。