ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Benjin Chen,Liang Xiao,Wanni Wang,Lingling Xu,Yechun Jiang,Guoqiang Zhang,Lin Liu,Xiaohu Li,Yongqiang Yu,Haisheng Qian
Radiotherapy efficacy was greatly limited by hypoxia and overexpression of glutathione (GSH) in the tumor microenvironment (TME), which maintained the immunosuppressive microenvironment and promoted DNA repair. In this work, 4T1 cell membrane-coated Bi2–xMnxO3 nanospheres have been achieved via a facile protocol, which showed enhanced therapeutic efficacy for a combination of radiotherapy and immunotherapy. Bi2–xMnxO3 nanospheres showed appreciable performance in generating O2 in situ and depleting GSH to amplify DNA damage and remodel the tumor immunosuppressive microenvironment, thus enhancing radiotherapy efficacy. Cancer cell membrane-coated Bi2–xMnxO3 nanospheres (T@BM) prolonged blood circulation time and enriched the accumulation of the materials in the tumor. Meanwhile, the released Mn2+ could activate STING pathway-induced immunotherapy, resulting in the immune infiltration of CD8+ T cells on in situ mammary tumors and the inhibition of pulmonary nodules. As a result, approximately 1.9-fold recruitment of CD8+ T cells and 4.0-fold transformation of mature DC cells were observed compared with the phosphate-buffered saline (PBS) group on mammary tumors (in situ). In particular, the number of pulmonary nodules significantly decreased and the proliferation of pulmonary metastatic lesions was substantially inhibited, which provided a longer survival period. Therefore, T@BM exhibited great potential for the treatment of 4T1 tumors in situ and lung metastasis.
研究领域:
癌症治疗
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纳米医学
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免疫学
·
放射生物学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Yu Hei,Binhong Teng,Ziqian Zeng,Siqi Zhang,Qian Li,Jijia Pan,Zuyuan Luo,Chunyang Xiong,Shicheng Wei
Background Immune checkpoint blockades (ICBs) are a promising treatment for cancers such as melanoma by blocking important inhibitory pathways that enable tumor cells to evade immune attack. Programmed death ligand 1 monoclonal antibodies (aPDL1s) can be used as an ICB to significantly enhance the effectiveness of tumor immunotherapy by blocking the PD-1/PD-L1 inhibitory pathway. However, the effectiveness of aPDL1s may be limited by low selectivity in vivo and immunosuppressed tumor microenvironment including hypoxia.Purpose To overcome the limitations, we develop a multifunctional immunoliposome, called CAT@aPDL1-SSL, with catalase (CAT) encapsulated inside to overcome tumor hypoxia and aPDL1s modified on the surface to enhance immunotherapeutic effects against melanoma.Methods The multifunctional immunoliposomes (CAT@aPDL1-SSLs) are prepared using the film dispersion/post-insertion method. The efficacy of CAT@aPDL1-SSLs is verified by multiple experiments in vivo and in vitro.Results The results of this study suggest that the multifunctional immunoliposomes preserve and protect the enzyme activity of CAT and ameliorate tumor hypoxia. Moreover, the enhanced cellular uptake of CAT@aPDL1-SSLs in vitro and their in vivo biodistribution suggest that CAT@aPDL1-SSLs have great targeting ability,resulting in improved delivery and accumulation of immunoliposomes in tumor tissue.Finally, by activating and increasing the infiltration of CD8+ T cells at the tumor site, CAT@aPDL1-SSLs inhibit the growth of tumor and prolong survival time of mice,with low systemic toxicity.Conclusion In conclusion, the multifunctional immunoliposomes developed and proposed in this study are a promising candidate for melanoma immunotherapy, and could potentially be combined with other cancer therapies like radiotherapy and chemotherapy to produce positive outcomes.
研究领域:
肿瘤学
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免疫学
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药学
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生物技术
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产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2024
·
IF 5.4
Yuting Hou,Zhe Wang,Zhen Chen,Lan Shuai,Yifei Pei,Binbin Sun,Yuxin Jiang,Hongsheng Wang
It is difficult to obtain specific tumor antigens, which is one of the main obstacles in the development of tumor vaccines. The vaccines containing multivalent antigens are thought to be more effective in antitumor therapy. In this study, a mRNA encoding three neoantigens of melanoma were prepared and encapsulated into the mannosylated chitosan-modified ethosomes (EthsMC) to obtain a multivalent mRNA vaccine (MmRV) for transcutaneous immunization (TCI). MmRV can effectively induce maturation of dendritic cells, with a better performance than mRNA of a single neoantigen. TCI patches (TCIPs) loading MmRV or siRNA against PDL1 (siPDL1) were prepared and applied to the skin of melanoma-bearing mice. The results showed that TCIPs significantly increase the levels of TNF-α, IFN-γ, and IL-12 in both plasma and tumor tissues, inhibit tumor growth, as well as promote infiltration of CD4+ and CD8+ T cells in the tumor tissues. Furthermore, the combination of MmRV and siPDL1 showed much better antitumor effects than either monotherapy, suggesting a synergistic effect between the vaccine and PDL1 blocker. In addition, the treatment with the TCIPs did not cause damage to the skin, blood, and vital organs of the mice, showing good biosafety. To the best of our knowledge, this work is the first to construct a noninvasive TCI system containing MmRV and siPDL1, providing a convenient and promising approach for tumor treatment.
研究领域:
肿瘤学
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免疫学
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药学
·
生物技术
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产品关联
DOI
PubMed
高影响因子
CELL RESEARCH
·
2025
·
IF 25.9
Hu Hui-Hui,Wang Xuefeng,Lan Bin,Cheng Haili,Wen Hong,Chen Fangfang,Wu Jianfeng,Li Mengqi,Chen Jiazhou,Zhang Jinhui,Chen Dongxu,Lin Shiyu,Lin Jieyu,Yang Mingyang,Wu Zhenhua,Zheng Zhong-Zheng,Chen Fuqing,Zhou Jianyin,Chen Gang,Chen Yu,Deng Xianming,Zhang Chen-Song,Liu Jingfeng,Lin Sheng-Cai
Dysregulated metabolism in tumor tissues and para-tumor tissues alike can lead to immunosuppression, which may underlie cancer development. However, metabolic intervention as a therapeutic strategy has been of no avail. In this study, we explored the anti-cancer therapeutic effect of aldometanib, which specifically targets lysosome-associated aldolase to mimic glucose starvation and thereby activates lysosomal AMP-activated protein kinase (AMPK), a master regulator of metabolic homeostasis. We show that aldometanib inhibits the growth of hepatocellular carcinoma (HCC) in an AMPK-dependent manner, allowing hepatoma-bearing mice to survive to mature ages, although aldometanib does not possess cytotoxicity toward HCC or normal cells. Intriguingly, aldometanib exerts anti-cancer effects only in immune-competent host mice, but not in immune-defective mice. We also found that HCC tissues in aldometanib-treated mice were massively infiltrated with CD8 + T cells, which was not seen in mice with liver-specific knockout of AMPKα . Our findings thus suggest that the metabolic regulator AMPK rebalances the tumor microenvironment to allow cytotoxic immune cells inside the body to eliminate cancer cells and effectively contain the tumor tissues. The finding that metabolic intervention can make cancer a lifelong manageable disease may usher in a new era of cancer therapy.
研究领域:
肿瘤学
·
免疫代谢
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癌症免疫治疗
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分子生物学
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代谢调控
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产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2024
·Vol. 10
·期 1
·1-14
·
IF 6.1
Sun Bao-Ye,Wang Zhu-Tao,Chen Ke-Zhu,Song Yang,Wu Jing-Fang,Zhang Dai,Sun Guo-Qiang,Zhou Jian,Fan Jia,Hu Bo,Yi Yong,Qiu Shuang-Jian
Lymph node metastasis (LNM) facilitates distant tumor colonization and leads to the high mortality in patients with intrahepatic cholangiocarcinoma (ICC). However, it remains elusive how ICC cells subvert immune surveillance within the primary tumor immune microenvironment (TIME) and subsequently metastasize to lymph nodes (LNs). In this study, scRNA-seq and bulk RNA-seq analyses identified decreased infiltration of dendritic cells (DCs) into primary tumor sites of ICC with LNM, which was further validated via dual-color immunofluorescence staining of 219 surgically resected ICC samples. Tumor-infiltrating DCs correlated with increased CD8 + T cell infiltration and better prognoses in ICC patients. Mechanistically, β-catenin-mediated CXCL12 suppression accounted for the impaired DC recruitment in ICC with LNM. Two mouse ICC cell lines MuCCA1 and mIC-23 cells were established from AKT/NICD or AKT/YAP-induced murine ICCs respectively and were utilized to construct the footpad tumor LNM model. We found that expansion and activation of conventional DCs (cDCs) by combined Flt3L and poly(I:C) (FL-pIC) therapy markedly suppressed the metastasis of mIC-23 cells to popliteal LNs. Moreover, β-catenin inhibition restored the defective DC infiltration into primary tumor sites and reduced the incidence of LNM in ICC. Collectively, our findings identify tumor cell intrinsic β-catenin activation as a key mechanism for subverting DC-mediated anti-tumor immunity in ICC with LNM. FL-pIC therapy or β-catenin inhibitor could merit exploration as a potential regimen for mitigating ICC cell metastasis to LNs and achieving effective tumor immune control.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症免疫治疗
✓ 已验证
DOI
高影响因子
Small
·
2025
·
IF 12.1
Luoyingzi Xie,Jie Gong,Zhiqiang He,Weinan Zhang,Haoyu Wang,Shitao Wu,Xianxing Wang,Pijiang Sun,Lei Cai,Zhongjun Wu,Huaizhi Wang
Cancer is one of the most important challenges worldwide with an increasing incidence. However, most of patients with malignant cancer receiving traditional therapies have tumor recurrence and short-term 5-year survival. Herein, a novel Cu 2 O-MnO@PEG (CMP) nanomaterial is developed to treat tumors. CMP directly mediates cuproptosis in tumor cells. Meanwhile, CMP potentiates anti-tumor immune responses in the tumor microenvironment (TME) to induce tumor regression. CMP improves the tumor antigen processing and presentation of dendritic cells and tumor-associated macrophages, and further promotes CD8 + T cell responses, especially for cytotoxic CD8 + T cells and transitory exhausted CD8 + T cells. Additionally, CMP downregulates the proportion of Treg cells and CTLA-4 expression on Treg cells. Notably, CMP induces systemic immune responses against distant tumors and long-term immune memory. Furthermore, CMP synergized with PD-L1 mAb promotes tumor inhibition and sustains the anti-tumor efficacy post PD-L1 mAb treatment. Collectively, this strategy has the clinically therapeutic potential for tumors by facilitating cuproptosis in tumor cells and anti-tumor immune responses.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2017
·
IF 4.44
Chuangnian Zhang,Ju Zhang,Gaona Shi,Huijuan Song,Shengbin Shi,Xiuyuan Zhang,Pingsheng Huang,Zhihong Wang,Weiwei Wang,Chun Wang,Deling Kong,Chen Li
In this study, the photochemical internalization (PCI) technique was adopted in a nanoparticle-based antigen delivery system to enhance antigen-specific CD8+ T cell immune response for cancer immunotherapy. Pheophorbide A, a hydrophobic photosensitizer, grafted with polyethylenimine (PheoA-PEI) with endosome escape activity and near-infrared imaging capability was prepared. A model antigen ovalbumin (OVA) was then complexed with PheoA-PEI to form PheoA-PEI/OVA nanoparticles (PheoA-PEI/OVA NPs) that are responsive to light. Flow cytometry analysis revealed increased endocytosis in a murine dendritic cell line (DC2.4) that was treated with PheoA-PEI/OVA NPs compared to free OVA. Generation of reactive oxygen species (ROS) in DC2.4 cells was also confirmed quantitatively and qualitatively using 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA). Confocal laser scanning microscopy (CLSM) further demonstrated that the PheoA-PEI/OVA NPs enhanced cytosolic antigen release after light stimulation. Moreover, PheoA-PEI/OVA NP treated DC2.4 cells exhibited enhanced cross-presentation to B3Z T cell hybridoma in vitro after light irradiation, substantially increased compared to those treated with free OVA. Consistently, in vivo results revealed upregulation of CD3+CD8+T lymphocytes in tumors of mice treated with dendritic cells plus PheoA-PEI/OVA NPs and light irradiation. The activated T cell response is partly responsible for the inhibitory effect on E.G7 tumor growth in mice immunized with dendritic cells plus PheoA-PEI/OVA NPs and light irradiation. Our results demonstrate the feasibility to enhance antigen-specific CD8+ T cell immune response by light-responsive nanoparticle-based vaccine delivery for cancer immunotherapy.
研究领域:
纳米技术
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免疫学
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癌症研究
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药学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 9
·3740
·
IF 4.6
Jibing Zhang,Xiao Cui,Yujiao Huang,Xiangdong Xu,Changshun Feng,Jun Li
Breast cancer is one of the most common cancers worldwide, posing a serious threat to human health. Recently, innate immunity has become a widely discussed topic in antitumor research. The STING pathway is an important component of innate immunity, and several STING agonists have been developed and applied in antitumor research. Dimeric amidobenzimidazole (diABZI) is one STING agonist and is a nucleotide analog with low serological stability and cell membrane permeability. In this study, we prepared diABZI-encapsulated liposomes (dLNPs) using the ammonium sulfate gradient method. The average particle size of the dLNPs was 99.76 ± 0.230 nm, and the encapsulation efficiency was 58.29 ± 0.53%. Additionally, in vivo and in vitro assays showed that the dLNPs had a sustained-release effect and that the circulation time in vivo was longer than 48 h. The expression of IFN-β and IFN-γ was elevated in mice treated with dLNPs. Moreover, we found that dLNPs can recruit CD8+T cells to tumor tissue and exert antitumor effects. The dLNPs-treated group showed the most significant efficacy: the average tumor volume was 231.46 mm3, which decreased by 78.16% and 54.47% compared to the PBS group and diABZI group. Meanwhile, the hemolysis rate of the dLNPs was 2%, showing high biocompatibility. In conclusion, dLNPs can effectively suppress tumor growth and possess great potential in breast cancer therapy.Keywords:STING;agonist;liposomes;antitumor;breast cancer
研究领域:
肿瘤学
·
免疫疗法
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Lele Gong,Yuanyuan Zhang,Lele Wang,Xuyang Zhao,Lucai Wang,Xiangqi Qiu,Xilong Yang,Wenhui Zhu,Lijie Lv,Yunzhe Kang,Yanan Wu,Angke Zhang,Yongkun Du,Xuannian Wang,Gaiping Zhang,Aijun Sun,Guoqing Zhuang
The African swine fever virus (ASFV) continues to pose significant economic and pandemic risks. Consequently, discovering new, efficient vaccines is crucial. Messenger RNA (mRNA) vaccines have emerged as promising candidates, providing minimal risk of insertional mutagenesis, high safety profiles, effectiveness, rapid scalability in production, and cost-effectiveness. In this study, we have developed an ASF p30 mRNA vaccine candidate (mRNA/Man-LNP) employing mannose-modified lipid nanoparticles (LNPs). The mRNA/Man-LNP exhibited effective antigen presentation and facilitated dendritic cells (DCs) maturation. Notably, it elicited strong IgG titers and activated CD4 + and CD8 + T-cells in immunized mice, all while adhering to stringent biosafety standards. This investigation demonstrates that mRNA/Man-LNP can trigger both humoral and cellular immune responses, suggesting its potential as a potent and promising vaccine candidate for controlling African swine fever (ASF).
研究领域:
兽医学
·
免疫学
·
分子生物学
·
病毒学
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DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Weiting Jiang,Wei Deng,Qi Chen,Huahua Zhang,Min Zhu,Rongze Wang,Yong Wang
Pancreatic cancers are marked by a highly fibrotic extracellular matrix (ECM) that fosters an immunosuppressive tumor microenvironment (TME), severely limiting the effectiveness of traditional therapies. Emerging evidence suggests that ECM modulation represents a promising strategy to enhance treatment outcomes in pancreatic cancer. Herein, we developed a polymeric nanovesicle for the co-encapsulation and delivery of gemcitabine and prolyl isomerase Pin1 inhibitor sulfopin (Gem/Sul-NP). The engineered Gem/Sul-NP features a compact size of approximately 50 nm, facilitating improved accumulation and penetration within pancreatic tumor tissues. Additionally, the Gem/Sul-NP demonstrates pH-responsive characteristics, undergoing structural disintegration at the acidic pH of 6.5 to achieve controlled drug release in the TME, thereby facilitating synergistic antitumor effects. Sulfopin functions to inhibit pancreatic stellate cells (PSCs) activation, reducing ECM component secretion and disrupting stromal barriers. Besides, it upregulates the expression of the gemcitabine transporter equilibrative nucleoside transporter 1 (ENT1) on tumor cell membranes, thereby enhancing the cellular uptake of gemcitabine and its chemotherapeutic impact. Our in vivo studies confirmed that Gem/Sul-NP treatment effectively remodeled the immunosuppressive TME. When combined with anti-PD-1 therapy, this approach significantly increased CD8 + IFNγ + T cell infiltration, indicating its potential to create favorable conditions for synergistic chemoimmunotherapy against pancreatic cancers.
研究领域:
肿瘤学
·
纳米技术
·
药剂学
·
免疫学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2024
·
IF 27.7
Yu Jiang,Yawen Wang,Guofeng Chen,Fei Sun,Qijing Wu,Qiong Huang,Dongqiang Zeng,Wenjun Qiu,Jiao Wang,Zhiqi Yao,Bishan Liang,Shaowei Li,Jianhua Wu,Na Huang,Yuanyuan Wang,Jingsong Chen,Xiaohui Zhai,Li Huang,Beibei Xu,Masami Yamamoto,Tetsuya Tsukamoto,Sachiyo Nomura,Wangjun Liao,Min Shi
Immune checkpoint blockade has led to breakthroughs in the treatment of advanced gastric cancer. However, the prominent heterogeneity in gastric cancer, notably the heterogeneity of the tumor microenvironment, highlights the idea that the antitumor response is a reflection of multifactorial interactions. Through transcriptomic analysis and dynamic plasma sample analysis, we identified a metabolic “face-off” mechanism within the tumor microenvironment, as shown by the dual prognostic significance of nicotinamide metabolism. Specifically, macrophages and fibroblasts expressing the rate-limiting enzymes nicotinamide phosphoribosyltransferase and nicotinamide N-methyltransferase, respectively, regulate the nicotinamide/1-methylnicotinamide ratio and CD8+ T cell function. Mechanistically, nicotinamide N-methyltransferase is transcriptionally activated by the NOTCH pathway transcription factor RBP-J and is further inhibited by macrophage-derived extracellular vesicles containing nicotinamide phosphoribosyltransferase via the SIRT1/NICD axis. Manipulating nicotinamide metabolism through autologous injection of extracellular vesicles restored CD8+ T cell cytotoxicity and the anti-PD-1 response in gastric cancer.
研究领域:
肿瘤学
·
免疫学
·
代谢学
·
癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Pingting Ye,Chunhui Wang,Yixuan Wen,Kang Fang,Qi Li,Xin Zhang,Jingxian Yang,Ruihao Li,Mengyao Chen,Xiaohan Tong,Shuo Shi,Chunyan Dong
Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer due to poor immunogenicity and limited immune cell infiltration, efficient therapeutics are still deficiency. Ferroptosis, a reactive oxygen species (ROS)-reliant cell death, can enhance cellular immunogenicity and then active immune system. To sustain a long-term “hot” tumour immune microenvironment (TIME), an immune-modulator is indispensable. Metformin (MET), a commonly used oral drug for type 2 diabetes, has played a vital role in fostering an immunostimulatory environment. Herein, we confirm the TIME can be remodeled by MET and further promotes ferroptosis via upregulating cellular concentration of l -Glutamine. In light of this, we have design a self-assembled MET-loaded Fe 3+ -doped polydopamine nanoparticle (Fe-PDA-MET NP) that can disorder the cellular redox homeostasis and induce robust ferroptosis under 808 nm irradiation, resulting in a strong immune response. Based on the function of MET, there is a marked increase in the infiltration of activated CD8 + T cells and NK cells, which subsequently augments ferroptosis to a greater extent. Taken together, Fe-PDA-MET NPs activate a ferroptotic positive-feedback loop for effectively control TNBC progression, which offers a promising therapeutic modality to enhance the immunogenicity and reshape the TIME.
研究领域:
肿瘤学
·
免疫疗法
·
纳米技术
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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