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WIREs Nanomed Nanobiotechnol
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Regulation of cancer‐immunity cycle and tumor microenvironment by nanobiomaterials to enhance tumor immunotherapy

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Abstract In the past decade, we have witnessed the revolution in cancer therapy, especially in the rapid development of cancer immunotherapy. In particular, the introduction of nanomedicine has achieved great improvement in breaking the limitations of and immunological tolerance caused by clinic‐approved immunotherapies (cancer vaccine, CAR‐T, and immune checkpoint blockade) to enhance immunogenicity, antigen presentation and T lymphocyte infiltration for eradicating the primary tumors and distant metastases simultaneously. However, some fundamental but significant issues still need to be thoroughly clarified before the combination of nanomedicine and immunotherapy moves toward clinical translation such as biological safety and synergistic mechanisms of nanomaterials in the systematic immune responses. Therefore, in this review, the role of nanomaterials in cancer immunotherapy is summarized, mainly focusing on the effective activation and long‐term stimulation of both the innate and the adaptive immune responses and regulation of or remodeling the tumor microenvironment, especially the tumor immunosuppressive microenvironment. Also, we elaborate on the targets and challenges of nanomaterials in the cancer‐immunity cycle, summarize several main strategies to convert the cold tumor immune microenvironment to the hot one, and illustrate the progress in regulation of tumor immune microenvironment by targeting specific immunosuppressive cells. Finally, we prospect the nano‐combined immunotherapy strategies in tumor‐targeting, normalization of tumor immune environment and modification of macrophages. This article is characterized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Schematic illustration of the synthesis of ROS‐responsive hydrogel scaffold nanosystem in situ and evaluation of antitumor immune response in vivo. (a) Scheme of chemo‐immunotherapy combination therapy using a ROS‐degradable hydrogel scaffold to deliver chemotherapeutics (gemcitabine, GEM) and immune checkpoints blockade antibody (anti‐PD‐L1) into the TME. (b) Evaluation of systemic immune response induced by detecting the ratios of the tumor‐infiltrating CD8+ T cell, CD4+ T cell and Tregs cell phenotypes in tumors with B16F10 melanoma‐bearing mouse model. (Reprinted with permission from Wang et al. (). Copyright 2018 American Association for the Advancement of Science)
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Strategies of combination cancer immunotherapy on the basis of the nanocarrier. Nanoparticle (NP), as the vehicle, could deliver tumor antigens/adjuvant which induces DCs maturation and restores T cell antitumor function by loading CTLA‐4 or PD‐1/PD‐L1 antibodies. (Reprinted with permission from Qiu, Min, Rodgers, Zhang, and Wang (). Copyright 2017 Wiley Periodicals, Inc.)
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Illustration of the design of multi‐stimuli triggered smart nanoparticles in the tumor microenvironment. Both [email protected]/F68 (a) and TENAB (b) nanoparticles could response to hypoxia and low pH in the tumor microenvironment for cancer synergistic therapy. (Reprinted with permission from Chen, Deng, Liu, et al. (); Chen, Tang, Zhu, et al. (). Copyright 2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim, and Elsevier Ltd.)
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Overview of aims of cancer immunotherapies in clinical trials and corresponding immunosuppressive factors. Traditional therapies (e.g., radiotherapy, chemotherapy, and phototherapy) can directly kill tumor cells and generate “vaccine pool” in situ to initiate the immune response. This response is limited by tolerogenic cell death. Vaccine transplant focuses on facilitating the antigen presentation and activation of T cells subsequently. These processes are suppressed by immunosuppressive factors (e.g., IL‐10, IL‐4, and IL‐13). Specific CTLs infiltrate into primary tumors and metastases to initiate tumor killing. CAR‐T cell therapy aims to these links by re‐training and expanding T cells ex vivo and infusing back to patients. Usually, the insufficient immunological effect is extensively restricted by the complicated tumor microenvironment (TME) through checkpoint pathways (PD‐L1/PD‐1), various immunosuppressive cells such as regulatory T cells (Tregs), myeloid‐derived suppressor cells (MDSCs), and tumor‐associated macrophages (TAMs). CTLA‐4, CTL‐associated protein‐4; PD‐1, programmed death‐1
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Schematic illustration of the process of the cancer‐immunity cycle. The illustration of cycle mainly be summarized as seven steps: (1) release of tumor‐associated antigens (TAAs); (2) recognition and presentation of TAAs by antigen‐presenting cells (APCs); (3) priming and activation T cells in lymph gland; (4, 5) trafficking and infiltration of CTLs into tumors; and (6, 7) recognition and killing of cancer cells by CTLs. The position where each step occurs is also annotated in the diagram. (Reprinted with permission from Chen and Mellman (). Copyright 2013 Elsevier Inc.)
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Nanoparticles enhance immunotherapy by targeted remodeling of immunosuppressive cells in TME. Strategies for targeting (a) and the main reported nanoparticles (b) for remodeling the TME are shown. (Reprinted with permission from Gao et al. (). Copyright 2019 Ivyspring International Publisher)
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Schematic illustration to show the strategies for relieving hypoxia in tumors. (a) Perfluorocarbon (PFC) nanodrop delivered the O2 to the tumor site under the ultrasound stimulation for enhanced radiotherapy and photodynamic therapy. (b) Application of manganese dioxide (MnO2)‐based core‐shell semiconducting nanoparticles to convert endogenous H2O2 to O2 under the hypoxic and acidic responses in the tumor microenvironment. (c) Self‐sufficiency of O2 in tumor photodynamic therapy was achieved by using exogenous catalase. (Reprinted with permission from Song, Liang, et al. (). Copyright 2016; Zhu et al. (). Copyright 2018 and Chen et al. (). Copyright 2015 American Chemical Society)
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The paradigm of immunological responses evoked by photothermal therapy with/without immunologic adjuvant. (a) Schematic illustration of the preparation of the NIR‐II‐triggered PTT based on self‐assembly of Au nanoparticles to promotes innate and adaptive anti‐cancer immunity. (b) Scheme showing an immunologic adjuvant (CpG)‐loaded superparamagnetic iron oxide nanoagent (MINPs) triggered immunotherapy under the magnetic stimulation for ablation of both primary‐treated and distant‐untreated tumors. (Reprinted with permission from Ma et al. (). Copyright 2019 American Chemical Society and Guo et al. (). Copyright 2019 Elsevier Ltd.)
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The strategy of enhanced photodynamic‐immunotherapy by repeated stimulations via light‐triggered gelation system. (a) Design and characterization of light‐triggered, in situ formation of the Ce6‐CAT/PEGDA hydrogel system. (b) Schematic illustration of combining local PDT with immune checkpoint blocking (α‐CTLA4) therapy for mechanism studies. (c–e) Analysis of the proportions of tumor‐infiltrating effector CD8+ T cells (c), effector Treg cells (d), and CD8+ CTL to Treg ratios (e) in distant tumors posttreatment at the appointed time. (Reprinted with permission from Meng et al. (). Copyright 2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim)
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Mechanism of immune abscopal effect induced by photodynamic therapy (PDT) and photothermal therapy (PTT) to eradicate residual tumor cells in situ and metastasis at distant site post‐conventional‐phototherapy. (Reprinted with permission from Li, Li, et al. (). Copyright 2019 Elsevier B.V.)
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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