Acta Biomaterialia
·
2024
·
IF 9.4
Siyuan Luo,Yueyan Yang,Liuting Chen,Perumal Ramesh Kannan,Weili Yang,Yongjia Zhang,Ruibo Zhao,Xiaoli Liu,Yao Li,Xiangdong Kong
Tumor hypoxia, high oxidative stress, and low immunogenic create a deep-rooted immunosuppressive microenvironment, posing a major challenge to the therapeutic efficiency of cancer immunotherapy for solid tumor. Herein, an intelligent nanoplatform responsive to the tumor microenvironment (TME) capable of hypoxia relief and immune stimulation has been engineered for efficient solid tumor immunotherapy. The MnO 2 @OxA@OMV nanoreactor, enclosing bacterial-derived outer membrane vesicles (OMVs)-wrapped MnO 2 nanoenzyme and the immunogenic cell death inducer oxaliplatin (OxA), demonstrated intrinsic catalase-like activity within the TME, which effectively catalyzed the endogenous H 2 O 2 into O 2 to enable a prolonged oxygen supply, thereby alleviating the tumor's oxidative stress and hypoxic TME, and expediting OxA release. The combinational action of OxA-caused ICD effect and Mn 2+ from nanoreactor enabled the motivation of the cGAS-STING pathway to significantly improve the activation of STING and dendritic cells (DCs) maturation, resulting in metalloimmunotherapy. Furthermore, the immunostimulant OMVs played a crucial role in promoting the infiltration of activated CD8 + T cells into the solid tumor. Overall, the nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy. Statement of Significance A tailor-made nanoreactor was fabricated by enclosing bacterial-derived outer membrane vesicles (OMVs) onto MnO 2 nanoenzyme and loading with immunogenic cell death inducer oxaliplatin (OxA) for tumor metalloimmunotherapy. The nanoreactor possesses intrinsic catalase-like activity within the tumor microenvironment, which effectively enabled a prolonged oxygen supply by catalyzing the conversion of endogenous H 2 O 2 into O2, thereby alleviating tumor hypoxia and expediting OxA release. Furthermore, the TME-responsive release of nutritional Mn 2+ sensitized the cGAS-STING pathway and collaborated with OxA-induced immunogenic cell death (ICD). Combing with immunostimulatory OMVs enhances the uptake of nanoreactors by DCs and promotes the infiltration of activated CD8 + T cells. This nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy.
研究领域:
癌症免疫疗法
·
纳米技术
·
生物材料
·
肿瘤生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Aggregate
·
2025
·
IF 13.7
Xiaojiang Zhang,Yujie Zhang,Pengqian Wang,Feiyu Shi,Siyuan Du,Zhe Zhang,Daocheng Wu,Junjun She,Ya Wang
To improve the long-term therapeutic efficacy of colorectal cancer, we propose a synergistic treatment strategy involving dual-pathway, multistep induction of long-term hyperimmunity combined with photothermal-chemotherapy. To implement this strategy, infinite coordination polymer nanoparticles (SN38-Mn(II)-EGCG ICP NPs) were prepared by coordinating SN38, EGCG, and Mn 2+ . These nanoparticles were then coated with polydopamine (PDA) and grafted with folate-PEG-thiol (FA-PEG-SH) onto their surfaces, producing tumor-targeting folate-modified PDA infinite coordination polymer nanocomposites (ICP@FA-PDA nanocomposites). These nanocomposites exhibit a particle size of 94.9 ± 1.6 nm with a high drug loading capacity (83.3% ± 1.5%), drug release under acidic conditions while maintaining stability in physiological environments. Furthermore, each component within the nanocomposites serves multiple functions. Notably, the incorporation of multiple components triggers a powerful antitumor immune effect and establishes enduring immune memory through a dual-pathway and multistep approach, which is produced with the activation of the cGAS-STING pathway and immunogenic cell death (ICD) by a four-component multistep process. Under a low-dose regimen, this approach induces dual-pathway hyperimmunity effect and generates ultra-long immunological memory, marked by a ninefold increase in CD8 + T cell infiltration, a fourfold increase in CD4 + T lymphocytes, a fourfold reduction in Treg cells, and a fivefold increase in memory T cells. The remarkable therapy efficacy is achieved by hyperimmunity effect combination of SN38 and EGCG chemotherapy and photothermal therapy. In vivo studies demonstrated that mice treated with ICP@FA-PDA nanocomposites achieved complete eradication of cancer within 21 days, with no recurrence observed within 60 days. These nanocomposites hold significant promise and potential for future clinical translation.
研究领域:
癌症治疗
·
纳米医学
·
免疫学
·
化学
·
生物材料
✓ 已验证
产品关联
DOI
高影响因子
CANCER LETTERS
·
2020
·
IF 7.36
Huimin Tao,Lu Cheng,Lihua Liu,Hong Wang,Zhijie Jiang,Xu Qiang,Lijun Xing,Yifeng Xu,Xinying Cai,Jing Yao,Min Wang,Zheng Qiu
Antibodies blocking the PD-1/PD-L1 pathway have achieved great success. However, some disadvantages of antibodies have been found, which limit their clinical applications. Peptide antagonists are alternatives to antibodies in PD-1/PD-L1 blockage, but successful studies in this area are limited. A PD-1 targeting peptide, P–F4, was identified using phage display. P–F4 bound PD-1 with an affinity of 0.119 μM, inhibited PD-1/PD-L1 interaction at the cellular level and modulated T cell activity in vitro . We have overcome the poor solubility and rapid degradation problems of this peptide by packaging P–F4 in nanoparticles. In vivo experiments demonstrated that P–F4 nanoparticles could strongly inhibit tumor growth in a CT26 mouse model. Further research revealed that treatment of P–F4 nanoparticles increased CD8+T cells and reduced Tregs in the tumor microenvironment and tumor-draining lymph nodes. It was shown that treatment of P–F4 nanoparticles also increased lymphocytic activities, including proliferation, cytokine secretion and cytolytic activity. Moreover, computer modeling suggested that the P–F4 binding site to PD-1 overlaps with the PD-L1 binding surface. In this study, a peptide candidate for cancer immunotherapy was provided, and its working mechanisms were studied.
研究领域:
癌症免疫疗法
·
药学
·
免疫学
·
生物技术
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2022
·
IF 18.027
Gui Chen,Qing Xu,Zhenzhen Feng,Qinqin Xu,Xuhui Zhang,Yuanyuan Yang,Yuxuan Zhang,Xing-Jie Liang,Zhiqiang Yu,Meng Yu
Electrodynamic therapy (EDT) combining nanotechnology with electronic current was used in this study to generate highly cytotoxic oxidative hydroxyl radicals (·OH) for tumor destruction. However, increasing evidence suggests that EDT treatment alone for one time still faces great challenges in achieving long-term tumor suppression in an immunosuppressive environment, which would raise the risk of later tumor recurrence. Benefitting from the marvelous potential of reactive oxygen species (ROS)-mediated dynamic therapies in tumor immunocombination therapy due to their immunogenic cell death (ICD) effect, a glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON)-loaded nanocarrier (Pt–Pd@DON) was designed for combination therapy (EDT and immunotherapy) against tumor recurrence and metastasis. The protective immune response was motivated in highly immunosuppressive tumors by the joint functions of ICD and CD8+ T cell infiltration promoted by DON. A great therapeutic efficacy has been demonstrated in primary and metastatic tumor models, respectively. This study has provided an effective thought way for clinical highly immunosuppressive tumor treatment.
研究领域:
肿瘤学
·
免疫治疗
·
纳米医学
·
癌症生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2023
·
IF 7
Yu-Rong Zhan,Xi He,Zhi-Ying Huang,Ping Chen,Miao-Miao Tian,Guo-Hong Li,Xiao-Qi Yu,Xiang-Rong Song,Ji Zhang
The inefficient treatment using protein-based nanovaccines is largely attributed to their inadequate immunogenicity. Herein, we developed a novel fluoropolymer (PF) via ring-opening polymerization and constructed a fluoropolymer-based nanovaccine for tumor immunotherapy. Due to the existence of fluoroalkyl chains, PF not only played a crucial role in tumor antigen delivery but also exhibited a remarkable adjuvant effect in enhancing the immunogenicity of nanovaccines. The nanovaccines formed by mixing PF with a model antigen ovalbumin (OVA) enhanced the uptake of antigen proteins by dendritic cells (DCs) and promoted the maturation and antigen presentation of DCs. Compared with free OVA, PF/OVA showed better efficacy in both pre-cancer prevention and tumor treatment. Furthermore, the proportion of CD4+ T and CD8+ T cells was significantly increased in lymph nodes and tumors of mice immunized with PF/OVA. Additionally, there was a great enhancement in the levels of key anti-tumor cytokines (TNF-α and IFN-γ) in the serum of the PF/OVA immunized mice. Our research has shown that fluoropolymer PF applied as a protein vector and adjuvant has great potential for the development of nanovaccines with robust immunogenicity.
研究领域:
癌症免疫学
·
药学
·
纳米技术
·
免疫治疗
✓ 已验证
DOI
PubMed
高影响因子
Cancer Immunology Research
·
2022
·Vol. 10
·期 4
·525-539
·
IF 12.02
Chen Yu,Cai Qiaomei,Pan Chaohu,Liu Wancheng,Li Lili,Liu Junxiao,Gao Meiling,Li Xiaorong,Wang Liguo,Rao Yu,Yang Heng,Cheng Genhong
Inhibitors of cyclin-dependent kinase-2 (CDK2) are commonly used against several solid tumors, and their primary mechanisms of action were thought to include cell proliferation arrest, induction of cancer cell apoptosis and induction of differentiation. Here, we found that CDK2 inhibition by either small molecular inhibitors or genetic Cdk2 deficiency promoted antitumor immunity in murine models of fibrosarcoma and lung carcinoma. Mechanistically, CDK2 inhibition reduced phosphorylation of RB protein and transcription of E2F-mediated DNA methyltransferase 1 (DNMT1), which resulted in increased expression of endogenous retroviral RNA and type I IFN (IFN-I) response. The increased IFN-I response subsequently promoted antitumor immunity by enhancing tumor antigen presentation and CD8 + T-cell infiltration. Our studies provide evidence that inhibition of CDK2 in cancer cells suppresses tumor growth by enhancing antitumor immune responses in the tumor microenvironment, suggesting a new mechanism to enhance antitumor immunity by CDK2 inhibitors.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2020
·
IF 7.182
Wei Xu,Sijia Fang,Yong Wang,Xiaoqing Chi,Xiaodan Ma,Tao Zhang,Songhua Hu
The present study was to investigate the molecular mechanism underlying lymphocyte activation by total polysaccharides from Atractylodis macrocephalae (RAMPtp). The results showed that RAMPtp significantly promoted the secretions of cytokines (IFN-γ, IL-1α, IL-21, IFN-α, CCL4, CXCL9 and CXCL10), increased the proportions of CD4 + and CD8 + subpopulations, and enhanced the expressions of c-JUN, NFAT4, STAT1 and STAT3. microRNA sequencing identified 67 differentially expressed miRNAs (DEMs) in RAMPtp-stimulated SMLN lymphocytes, including 55 up-regulated and 12 down-regulated. GO and KEGG enrichment analyses of the predicted DEMs-targeted genes indicated that they were associated with immune system pathways, including PI3K-Akt, MAPKs, Jak-STAT and Calcium signaling pathways, which were confirmed by western blot and pathway inhibition assays. RAMPtp was further observed to favor immunostimulatory effect on both T and B lymphocytes via binding to TCR and membrane Ig individually. These findings might explain the immunomodulatory mechanism of RAMPtp in ameliorating the bovine intramammary infection.
研究领域:
免疫学
·
分子生物学
·
兽医学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Xinying Liu,Baohui Liu,Conglong Chen,Chaowei Hong,Jia Xu,Yixuan Ruan,Ling Huang,Shanni Hong,Wei Chen,Ye Kuang
A significant challenge in modern radiotherapy (RT) is to minimize the detrimental effects on adjacent healthy tissues while concurrently increasing the susceptibility of tumor tissue to radiation. Investigating nanoradiosensitizers with multifunctional properties has a lot of potential as a highly effective strategy for augmenting the efficacy of RT. A novel Janus Ag/Fe-HfO 2 nanoparticle was synthesized in a single-step process. This versatile nanoradiosensitizer combines photothermal capabilities, enzyme-like activities, and the capacity for magnetic resonance imaging (MRI). The surfaces have been meticulously engineered with PEG to boost biocompatibility and adorned with RGD-targeting peptides that selectively target tumor cells (Ag/Fe-HfO 2 -PEG-RGD). The characterization results have demonstrated the successful preparation of Janus Ag/Fe-HfO 2 nanoparticles with a diameter of roughly 10 nm. Furthermore, the photothermal properties, MRI ability, and enzymatic catalytic activities (generate O 2 , produce hydroxyl radical, and consume GSH) of Ag/Fe-HfO 2 -PEG-RGD were verified in vitro experiments. In vivo experiments, by integrating T 1 -weighted MRI-guided RT with the enzymatic activities of these nanoparticles, along with the application of photothermal heating, we have achieved a synergistic enhancement in the therapeutic efficacy of RT. Moreover, it stimulates tumor-specific immune responses, leading to an increased presence of tumor-infiltrating CD8 + T cells. This integrated multimodal nanotherapeutic platform, which capitalizes on the potent enhancement of RT effects, offers a promising new strategy in the ongoing battle against cancer.
研究领域:
纳米医学
·
肿瘤学
·
放射治疗
·
磁共振成像
·
生物无机化学
·
诊疗一体化
·
免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Wei Duan,Rendy Hosea,Lingxian Wang,Cao Ruan,Fuqiang Zhao,Jingyi Liu,Hezhao Zhao,Makoto Miyagishi,Shourong Wu,Vivi Kasim
Immune checkpoint inhibitor (ICI) therapy is a promising anti-tumor therapeutic strategy; however, its efficacy in solid tumors is limited. Chromosome missegregation is common in various solid tumors; however, its role in tumor progression remains poorly understood, and its correlation with ICI is yet to be explored. Here, it is found that increased chromosome missegregation promotes tumor immune microenvironment, and eventually immunotherapeutic efficacy, by triggering pyroptosis. yin yang 2 (YY2) is identified as a mitotic checkpoint regulator, which promotes chromosome missegregation by upregulating BUB1B transcription. Increased chromosome missegregation promoted the formation of micronuclei and release of double-stranded DNA (dsDNA) into the cytosol, triggering an AIM2-mediated cytosolic dsDNA response. The subsequent pyroptosis strengthened the tumor immune microenvironment, thereby enhancing immunoinfiltration and cytotoxicity of CD8 + T cells, while preventing their exhaustion. Finally, through in vitro and in vivo experiments, it is demonstrated that combining YY2 overexpression-induced chromosome missegregation/cytosolic dsDNA response and PD-1 inhibitor significantly enhanced the efficacy of ICI immunotherapy in microsatellite instable and microsatellite stable colorectal cancer cells. Together, these findings provide new insights on the role of chromosome missegregation in triggering cytosolic dsDNA response-mediated pyroptosis and modulating the tumor immune microenvironment, suggesting a novel strategy for improving ICI therapeutic efficacy in colorectal cancer.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-23
·
IF 10.6
Sun Daxi,Yu Liting,Wang Gang,Xu Yuxue,Wang Peng,Wang Ningning,Wu Zhengyan,Zhang Guilong,Zhang Jia,Zhang Yunjiao,Tian Geng,Wei Pengfei
Chemodynamic therapy represents a novel tumor therapeutic modality via triggering catalytic reactions in tumors to yield highly toxic reactive oxygen species (ROS). Nevertheless, low efficiency catalytic ability, potential systemic toxicity and inefficient tumor targeting, have hindered the efficacy of chemodynamic therapy. Herein, a rationally designed catalytic nanoplatform, composed of folate acid conjugated liposomes loaded with copper peroxide (CP) and chloroquine (CQ; a clinical drug) (denoted as CC@LPF), could power maximal tumor cytotoxicity, mechanistically via maneuvering endogenous and exogenous copper for a highly efficient catalytic reaction. Despite a massive autophagosome accumulation elicited by CP-powered autophagic initiation and CQ-induced autolysosomal blockage, the robust ROS, but not aberrant autophagy, underlies the synergistic tumor inhibition. Otherwise, this combined mode also elicits an early onset, above all, long-term high-level existence of immunogenic cell death markers, associated with ROS and aberrant autophagy -triggered endoplasmic reticulum stress. Besides, CC@LPF, with tumor targeting capability and selective tumor cytotoxicity, could elicit intratumor dendritic cells (mainly attributed to CQ) and tumor infiltrating CD8 + T cells, upon combining with PD-L1 therapeutic antibody, further induce significant anti-tumor effect. Collectively, the rationally designed nanoplatform, CC@LPF, could enhance tumor chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment. Graphical abstract
研究领域:
肿瘤学
·
纳米技术
·
免疫治疗
·
癌症生物学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
·
IF 9.4
Yadi Fan,Ruolin Zhang,Jingyu Shi,Feng Tian,Yu Zhang,Li Zhang,Guangfu Liao,Mo Yang
One of the primary challenges for immune checkpoint blockade (ICB)-based therapy is the limited infiltration of T lymphocytes (T cells) into tumors, often referred to as immunologically “cold” tumors. A promising strategy to enhance the anti-tumor efficacy of ICB is to increase antigen exposure, thereby enhancing T cell activation and converting “cold” tumors into “hot” ones. Herein, we present an innovative all-in-one therapeutic nanoplatform to realize local mild photothermal- and photodynamic-triggered antigen exposure, thereby improving the anti-tumor efficacy of ICB. This nanoplatform involves conjugating programmed death-ligand 1 antibody (aPD-L1) with gadolinium-doped near-infrared (NIR)-emitting carbon dots (aPD-L1@GdCDs), which displays negligible cytotoxicity in the absence of light. But under controlled NIR laser irradiation, the GdCDs produce combined photothermal and photodynamic effects. This not only results in tumor ablation but also induces immunogenic cell death (ICD), facilitating enhanced infiltration of CD8 + T cells in the tumor area. Importantly, the combination of aPD-L1 with photothermal and photodynamic therapies via aPD-L1@GdCDs significantly boosts CD8 + T cell infiltration, reduces tumor size, and improves anti-metastasis effects compared to either GdCDs-based phototherapy or aPD-L1 alone. In addition, the whole treatment process can be monitored by multi-modal fluorescence/photoacoustic/magnetic resonance imaging (FLI/PAI/MRI). Our study highlights a promising nanoplatform for cancer diagnosis and therapy, as well as paves the way to promote the efficacy of ICB therapy through mild photothermal- and photodynamic-triggered immunotherapy.
研究领域:
癌症治疗
·
纳米技术
·
免疫疗法
·
生物医学工程
·
医学成像
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNITY
·
2024
·
IF 25.5
Zhigang Nian,Yingchao Dou,Yiqing Shen,Jintang Liu,Xianghui Du,Yong Jiang,Yonggang Zhou,Binqing Fu,Rui Sun,Xiaohu Zheng,Zhigang Tian,Haiming Wei
As the most frequent genetic alteration in cancer, more than half of human cancers have p53 mutations that cause transcriptional inactivation. However, how p53 modulates the immune landscape to create a niche for immune escape remains elusive. We found that cancer stem cells (CSCs) established an interleukin-34 (IL-34)-orchestrated niche to promote tumorigenesis in p53-inactivated liver cancer. Mechanistically, we discovered that Il34 is a gene transcriptionally repressed by p53, and p53 loss resulted in IL-34 secretion by CSCs. IL-34 induced CD36-mediated elevations in fatty acid oxidative metabolism to drive M2-like polarization of foam-like tumor-associated macrophages (TAMs). These IL-34-orchestrated TAMs suppressed CD8 + T cell-mediated antitumor immunity to promote immune escape. Blockade of the IL-34-CD36 axis elicited antitumor immunity and synergized with anti-PD-1 immunotherapy, leading to a complete response. Our findings reveal the underlying mechanism of p53 modulation of the tumor immune microenvironment and provide a potential target for immunotherapy of cancer with p53 inactivation.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）