Cancer immunotherapies that harness the body's immune system to combat tumors have received extensive attention and become mainstream strategies for treating cancer. Despite promising results, some problems remain, such as the limited patient response rate and the emergence of severe immune‐related adverse effects. For most patients, the therapeutic efficacy of cancer immunotherapy is mainly limited by the immunosuppressive tumor microenvironment (TME). To overcome such obstacles in the TME, the immunomodulation of immunosuppressive factors and therapeutic immune cells (e.g., T cells and antigen‐presenting cells) should be carefully designed and evaluated. Nanoengineered synthetic immune niches have emerged as highly customizable platforms with a potent capability for reprogramming the immunosuppressive TME. Here, recent developments in nano‐biomaterials that are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy which are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy are highlighted.
Tumor immunotherapy is only effective in a fraction of patients due to a low response rate and severe side effects, and these challenges of immunotherapy in clinics can be addressed through induction of immunogenic cell death (ICD). ICD is elicited from many antitumor therapies to release danger associated molecular patterns (DAMPs) and tumor‐associated antigens to facilitate maturation of dendritic cells (DCs) and infiltration of cytotoxic T lymphocytes (CTLs). The process can reverse the tumor immunosuppressive microenvironment to improve the sensitivity of immunotherapy. Nanostructure‐based drug delivery systems (NDDSs) are explored to induce ICD by incorporating therapeutic molecules for chemotherapy, photosensitizers (PSs) for photodynamic therapy (PDT), photothermal conversion agents for photothermal therapy (PTT), and radiosensitizers for radiotherapy (RT). These NDDSs can release loaded agents at a right dose in the right place at the right time, resulting in greater effectiveness and lower toxicity. Immunotherapeutic agents can also be combined with these NDDSs to achieve the synergic antitumor effect in a multi‐modality therapeutic approach. In this review, NDDSs are harnessed to load multiple agents to induce ICD by chemotherapy, PDT, PTT, and RT in combination of immunotherapy to promote the therapeutic effect and reduce side effects associated with cancer treatment.
Exosomes play important roles in cell-cell communication, and are likely mediators of the metastatic cascade in cancer. This study examined the role of exosomes in pancreatic cancer cell adhesion, migration, and invasion. We isolated and purified exosomes from two isogenic pancreatic cancer cell lines with different metastatic potentials. Uptake of exosomes from highly metastatic Panc02-H7 cells decreased adhesion and increased migration and invasion capacity in weakly metastatic Panc02 cells in vitro. Exosomes from highly metastatic pancreatic cancer cells induced liver pre-metastatic niche formation in naïve mice and promoted primary tumor growth and liver metastasis in vivo. We identified 4,517 proteins in exosomes from Panc02 and Panc02-H7 cells via iTRAQ quantitative proteomic analyses, 79 of which were differentially expressed between the two cell lines. Bioinformatics analyses showed that most of the differentially expressed proteins were involved in pancreatic cancer growth, invasion, and metastasis, and that metabolism-related signaling pathways were involved in exosome-mediated intracellular communication. Further studies will be needed to determine whether these proteins are potential pancreatic cancer diagnostic/prognostic markers or novel therapeutic targets.
Immune response in the tumor microenvironment (TME) is an essential therapeutic factor for antitumor therapy. Herein, to improve immunostimulatory effects, photodynamic therapy (PDT) is combined with AZD2281 to trigger the stimulator of interferon genes (STING)-dependent immune responses. A synthetic branched polymer-pyropheophorbide a (Ppa) conjugate (BGSSP) is designed and developed in response to redox/cathepsin B of the TME. This conjugate with a unique structure and a large molecular weight (MW) can self-assemble into a compact structure via hydrophilic and hydrophobic forces, inducing self-quenching of conjugated Ppa. AZD2281 is encapsulated in BGSSP to obtain a TME-activatable photodynamic nanoagent, AZD@BGSSP. AZD@BGSSP with a stable assembly structure accumulates effectively in tumors and enters lysosomes through endocytosis pathways. Polymer degradation, Ppa activation, and AZD2281 release are achieved after exposure of AZD@BGSSP to highly expressed cathepsin B and glutathione in tumor cells. After laser irradiation, AD2281 inhibits the repair of damaged DNA caused by ROS from PDT and promotes generation of cytosolic DNA, which activates the cGAS-STING pathway and further induces interferons-mediated immune responses and a long-term immune memory effect for immunotherapy. This nanoagent opens a new door to combination PDT and immune response for anti-cancer treatment.
The presence of immunosuppressive cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) in residual tumors after surgery is known to be related to high recurrence of tumors which are more resistant to therapeutic interventions compared with the primary ones. Herein, a degradation-regulatable architectured implantable macroporous scaffold (Dr-AIMS) is designed to control the immunosuppressive tumor microenvironments (TMEs) as well as to activate T-cell-based antitumor immunity. The Dr-AIMS is fabricated by the combination of stable "bulk" material (methacrylate-modified hyaluronic acid) and hydrolytic-labile "sacrificing" component (methacrylate-modified oxidized hyaluronic acid) with varied blending ratios such that the degradation can be regulated from 10 to 28 days in vivo. The Dr-AIMS is loaded with PTX (depleting cancer cells and TAMs), R837 (activating antigen presenting cells and inhibiting MDSCs functions) and combined immune checkpoint blockade molecules (anti-CTLA-4 and anti-OX40 mAbs, invigorating T cells function) and is implanted as postsurgical treatment in 4T1 breast tumor model. In vivo results suggest the sustained and localized supply of immunomodulatory drugs from Dr-AIMS facilitates the depletion of MDSCs and M2-like macrophages simultaneously within the tumor tissues, enhances the infiltration of DCs and effector T cells into tumor, and systemic antitumor immunity is generated with reduced dose.
Amorphization and crystalline grain boundary engineering are adopted separately in improving the catalytic kinetics for water electrolysis. Yet, the synergistic effect and advance in the cooperated form of crystalline/amorphous interfaces (CAI) have rarely been elucidated insightfully. Herein, a trimetallic FeCo(NiS 2 ) 4 catalyst with numerous CAI (FeCo(NiS 2 ) 4 -C/A) is presented, which shows highly efficient catalytic activity toward both hydrogen and oxygen evolution reactions (HER and OER). Density functional theory (DFT) studies reveal that CAI plays a significant role in accelerating water electrolysis kinetics, in which Co atoms on the CAI of FeCo(NiS 2 ) 4 -C/A catalyst exhibit the optimal binding energy of 0.002 eV for H atoms in HER while it also has the lowest reaction barrier of 1.40 eV for the key step of OER. H 2 O molecules are inclined to be absorbed on the interfacial Ni atoms based on DFT calculations. As a result, the heterostructural CAI-containing catalyst shows a low overpotential of 82 and 230 mV for HER and OER, respectively. As a bifunctional catalyst, it delivers a current density of 10 mA cm −2 at a low cell voltage of 1.51 V, which enables it a noble candidate as metal-based catalysts for water splitting. This work explores the role of CAI in accelerating the HER and OER kinetics for water electrolysis, which sheds light on the development of efficient, stable, and economical water electrolysis systems by facile interface-engineering implantations.
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