eLife
·
2022
·
IF 8.713
Zhenzhen Wang,Ziyu Zhai,Chunyu Chen,Xuejiao Tian,Zhen Xing,Panfei Xing,Yushun Yang,Junfeng Zhang,Chunming Wang,Lei Dong
Although fine particulate matter (FPM) in air pollutants and tobacco smoke is recognized as a strong carcinogen and global threat to public health, its biological mechanism for inducing lung cancer remains unclear. Here, by investigating FPM’s bioactivities in lung carcinoma mice models, we discover that these particles promote lung tumor progression by inducing aberrant thickening of tissue matrix and hampering migration of antitumor immunocytes. Upon inhalation into lung tissue, these FPM particles abundantly adsorb peroxidasin (PXDN) – an enzyme mediating type IV collagen (Col IV) crosslinking – onto their surface. The adsorbed PXDN exerts abnormally high activity to crosslink Col IV via increasing the formation of sulfilimine bonds at the NC1 domain, leading to an overly dense matrix in the lung tissue. This disordered structure decreases the mobility of cytotoxic CD8+ T lymphocytes into the lung and consequently impairs the local immune surveillance, enabling the flourishing of nascent tumor cells. Meanwhile, inhibiting the activity of PXDN abolishes the tumor-promoting effect of FPM, indicating the key impact of aberrant PXDN activity on the tumorigenic process. In summary, our finding elucidates a new mechanism for FPM-induced lung tumorigenesis and identifies PXDN as a potential target for treatment or prevention of the FPM-relevant biological risks.
研究领域:
肿瘤学
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免疫学
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环境健康
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2022
·
IF 14.903
Jingwen Dong,Chenfei Zhu,Ying Huang,Quanhao Li,Jing Li,Zheng Wang,Yixin Wang,Zhanwei Zhou,Minjie Sun
Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8 + T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.
研究领域:
癌症生物学
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免疫治疗
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药学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Open Medicine
·
2023
·Vol. 18
·期 1
·
IF 2.1
Jing Wang,Yiyu Shen,Xiaoguang Wang,Zhongcheng Zhou,Zhengxiang Zhong,Tianyuan Gu,Bin Wu
Our pre-investigation has revealed that long non-coding RNA (LncRNA) AL137789.1 has the potential to predict the survival of patients with pancreatic carcinoma (PCa). Accordingly, the mechanism underlying the implication of AL137789.1 in PCa is covered in the current study. The non-tumor and paired tumor tissues were collected. Kaplan–Meier curve was employed to estimate the survival of PCa patients with high or low expression of AL137789.1. The proliferation, migration, invasion, and cell cycle of PCa cells were determined, and the cytotoxicity of CD8 + T cells was evaluated as well. Levels of AL137789.1, E-cadherin, N-cadherin, and Vimentin were quantified. According to the experimental results, AL137789.1 was highly expressed in PCa and related to a poor prognosis of patients. Overexpressed AL137789.1 enhanced the proliferation, migration, and invasion of PCa cells, increased the cell population at G2/M and S phases yet decreased that in G0/G1 phase, and diminished the cytotoxicity of CD8 + T cells. Also, overexpressed AL137789.1 elevated levels of N-cadherin and Vimentin, while lessening E-cadherin levels. However, the silencing of AL137789.1 produced contrary effects. Collectively, lncRNA AL137789.1 plays a tumor-promotive role in PCa by enhancing the progression and immune escape.
研究领域:
肿瘤学
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分子生物学
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免疫学
✓ 已验证
DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Zhuoya Gao,Jiarong Zhang,Yingchao Hou,Jinjin Lu,Jing Liang,Yufeng Gao,Boqi Li,Shuai Gao,Yanjun Zhao,Min Gao,Jinghua Chen
Both ferroptotic therapy and immunotherapy have been widely employed in cancer treatment. However, ferroptotic cell death fails to induce dendritic cells maturation, which limits the therapeutic outcome of ferroptotic cancer therapy. To address this, the current work reports a tailored liposome to establish a positive loop between ferroptotic therapy and immunotherapy. As the key component of liposome, a unique phospholipid is designed to bear two arachidonic acid tails. The liposome is further surface-engineered with fucose ligand and physically encapsulates immunostimulatory CpG oligodeoxynucleotides (ODNs). The tailored liposome shows enhanced cellular uptake in a model 4T1 cell line. Meanwhile, the high level of reactive oxygen species in cancer cells can induce ferroptosis-specific peroxidation of DAPC and trigger the release CpG ODNs. The CpG ODNs further enable the maturation of dendritic cells and enhance the effector function of CD8 + T cells . IFN-γ released from CD8 + T cells promotes cancer cell ferroptosis via inhibiting SLC7A11 and suppressing the biosynthesis of glutathione . The tailored liposome can also act in synergism with PD-L1 antibody, resulting in enhanced anti-cancer efficacy in a 4T1 tumor-bearing mice model. This work provides a promising strategy for cancer treatment through orchestrating ferroptotic therapy and immunotherapy.
研究领域:
肿瘤学
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药学
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免疫学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2017
·
IF 8.402
Fei Duan,Xiaochen Feng,Xinjian Yang,Wentong Sun,Yi Jin,Huifang Liu,Kun Ge,Zhenhua Li,Jinchao Zhang
Tumor-associated antigens (TAAs)-loaded nanoparticles are able to be actively internalized by antigen-presenting cells (APCs) and have shown promising potential in cancer immunotherapy . However, current TAAs delivery strategy exhibits limitations of complicated synthesis process, low loading efficiency and inefficient CD8 + cytotoxic T lymphocyte activation leading to unsatisfactory therapeutic effect. Thus, the construction of novel TAAs-delivery systems for enhanced cancer therapy is highly desirable. In this work, we fabricated a very simple yet powerful antigens-delivery system for cancer immunotherapy based-on pH-responsive metal-organic frameworks (MOFs) with size about 30 nm. TAAs can be loaded into MOFs in the one-pot synthesis process and released with the degradation of MOFs in the acidic environment of endo/lysosome as the result of relatively labile metal-ligand bonds. The endosomolytic nanoparticles would facilitate protein antigens escape from endo/lysosome and optimal for enhancing antigen cross-presentation. Furthermore, the introduction of immunostimulatory unmethylated cytosine-phosphate-guanine oligonucleotide (CpG) through Watson−Crick base pairing would further enhance CD8 + cytotoxic T lymphocyte responses. We demonstrated that the method to co-delivery antigens and immunostimulatory molecules was very simple, convenient and effective and showed no obvious toxicity both in vitro and in vivo . This method gave a high antigens-loading capacity and the maximal antigen encapsulating efficiency was about 55% (w/w). Additionally, the pH-responsive co-delivery system exerted enhanced antitumor outcome (about 100% survival) in B16-OVA melanoma cancers in vivo . Furthermore, we confirmed that this high rating of therapeutic effect was attributed to the recruitment of tumor-killing immunocyte. This work demonstrates the ability of pH-responsive, endosomolytic MOFs to induce strong cellular immune responses for cancer therapy by co-delivery of CpG ODN and antigens.
研究领域:
生物医学工程
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免疫学
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癌症研究
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纳米技术
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Tao Bo,Chenfei Wang,Dingjin Yao,Qiuyu Jiang,Yitong Zhao,Feifei Wang,Wei He,Weiyi Xu,Hao Zhou,Ming Li,Si Zhang,Ruyi Xue
Gene delivery to macrophages holds great promise for cancer immunotherapy. However, traditional gene delivery methods exhibit low transfection efficiency in macrophages. The star -shaped topological structure of polymers is known to encapsulate genes inside their cores, thereby facilitating sustained release of the genetic material. Herein, combining the structural advantages of star polymers and the transfection advantages of poly (β-amino ester)s (PAEs), we developed a novel linear oligomer grafting-onto strategy to synthesize a library of multi-terminal star structured PAEs (SPAEs), and evaluated their gene delivery efficiency in various tissue cells. The transfection with human hepatocellular carcinoma cells (HepG2, HCC-LM3 cells and MHCC-97H cells), rat normal liver cells (BRL-3 A cells), human ovarian cancer cells (A2780 cells), African green monkey kidney cells (Vero cells), human cervical cancer cells (HeLa cells), human chondrosarcoma cells (SW1353 cells), and difficult-to-transfect human epidermal keratinocytes (HaCaT cells) and normal human fibroblast cells (NHF cells) showed that SPAEs exhibited superior transfection profile. The GFP transfection efficiency of top-performing SPAEs in HeLa cells (96.1%) was 2.1-fold, and 3.2-fold higher compared to jetPEI and Lipo3000, respectively, indicating that the star-shaped topological structure can significantly enhance the transfection efficiency of PAEs. More importantly, the top-performing SPAEs could efficiently deliver Nod2 DNA to difficult-to-transfect RAW264.7 macrophages, with a high transfection efficiency of 33.9%, which could promote macrophage M1 polarization and enhanced CD8+ T cell response in co-incubation experiments. This work advances gene therapy by targeting difficult-to-transfect macrophages and remodeling the tumor immune microenvironment.
研究领域:
生物技术
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药学
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免疫学
·
癌症研究
✓ 已验证
DOI
高影响因子
CANCER RESEARCH
·
2025
·
IF 16.6
Zhang Jie,Chen Weiwu,Zhang Chen,He Qian,Wang Xudong,Han Jiayu,Gao Peng,Wang Kunyu,Xie Haoze,Gao Feng,Guo Yining,Guo Wenhao,Jiang Haofei,Le Jing,Zang Ruichen,Mo Sisi,Fan Haobo,Zhu Xiaoxiao,Jiang Xinrong,Gao Fengbin,Yu Yanlan,Ding Guoqing,Chen Yicheng
PD-1 restrains effective killing of cancer cells by the immune system and is predominantly located on the surface of T cells or other immune cells. However, cancer cells also express PD-1 to varying degrees, which is commonly associated with a poor prognosis. Here, we investigated the regulation and function of PD-1 expression in prostate cancer (PCa) and revealed the impact on the tumor microenvironment. PD-1 expression in cancer cells positively correlated with Gleason grade and metastasis but negatively correlated with CD8+ T cell infiltration in PCa patients. PCa cells secreted PD-1 in exosomes that enhanced the activity of myeloid-derived suppressor cells (MDSCs) by activating JAK/STAT3 signaling. The activated MDSCs in turn reduced the infiltration of CD8+ T cells within the tumor, promoting tumor immune evasion. The ubiquitin-specific protease USP7 induced deubiquitination and elevated the abundance of PD-1 in PCa, and USP7 inhibition sensitized PCa tumors to anti-PD-1 antibody treatment. Given the modest efficacy of current immunotherapeutic approaches for PCa, strategies to inhibit the secretion of PD-1-bearing exosomes or USP7 function may emerge as promising immunostimulatory interventions for treating PCa.
研究领域:
癌症生物学
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免疫学
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分子生物学
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细胞信号传导
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泌尿学
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
World Journal of Gastrointestinal Oncology
·
2025
·Vol. 17
·期 9
·108892
·
IF 2.5
Wei Xie,Xue-Jian Li,Yu-Sen Zhong,Jie Fang,Hui Qi,Meng Yang,Hua-Zhong Ying,Chen-Huan Yu
BACKGROUND Immunotherapy that employs dendritic cells (DCs) to activate the patient’s immune system has emerged as a promising therapeutic strategy to combat cancer; however, effective targeting agents are still limited. Ginsenoside F4, as a rare ginsenoside found in Panax ginseng , exhibits stronger antitumor and immunomodulatory activities than primary ginsenosides. However, its therapeutic effects on various diseases remain limited. AIM To investigate the antitumor effect of Ginsenoside F4 and mechanism on the maturation of DCs in colorectal cancer (CRC). METHODS The changes in mature DC markers and cytokines generated after DCs were exposed to F4 were assessed using flow cytometry and enzyme-linked immunosorbent assay, respectively. The viability of CRC CT26 cells co-cultured with T lymphocytes was monitored by cell counting kit-8 assay. Furthermore, the histopathological characteristics and immune cell infiltration in tumor tissues of CT26-bearing mice were analyzed by hematoxylin-eosin and immunofluorescent staining. The expressions of apoptosis-relative proteins were detected by western blot assay. RESULTS Treatment with F4 promoted the maturation of DCs, elevated the expressions of cluster of differentiation (CD) 83 and CD86, increased the secretion of interleukin (IL)-2, IL-10, and IL-12 p70, and upregulated the expressions of phosphorylated phosphoinositide 3-kinase, phosphorylated protein kinase B, and nuclear factor kappa-B (NF-κB) phosphorylated p65 in DCs, which enhanced antigen-specific CD8+ T-cell responses. However, these benefits could be reversed by the sphingosine-1-phosphate 1 (S1PR1) inhibitor fingolimod hydrochloride. Furthermore, oral administration with F4 inhibited tumor growth and increased DC and CD8+ T-cell infiltration in the tumor tissues of CT26-bearing mice. CONCLUSION The results demonstrated that F4 inhibited the growth of CRC by maturing DCs through activating S1PR1-mediated phosphoinositide 3-kinase/protein kinase B and NF-κB pathways, which triggered the antitumor effects of CD8+ T cells. Therefore, F4 could serve as an antitumor immunomodulator for CRC treatment.
研究领域:
肿瘤学
·
免疫学
·
药理学
·
天然产物
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Quguang Li,Yifan Yan,Chunjie Wang,Ziliang Dong,Yu Hao,Minming Chen,Zhuang Liu,Liangzhu Feng
Autologous cancer vaccines represent a promising therapeutic approach against tumor relapse. Herein, a concise biomineralization strategy was developed to prepare an immunostimulatory autologous cancer vaccine through protein antigen-mediated growth of flower-like manganese phosphate (MnP) nanoparticles. In addition to inheriting the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING)-activating capacity of Mn 2+ , the resulting ovalbumin (OVA)-loaded MnP (OVA@MnP) nanoparticles with superior stability and pH-responsiveness enabled efficient priming of antigen-specific CD8 + T cell expansion through promoting the endo/lysosome escape and subsequent antigen cross-presentation of OVA. Resultantly, OVA@MnP vaccines upon subcutaneous vaccination elicited both prophylactic and therapeutic effects against OVA-expressing B16-F10 melanoma. Furthermore, the biomineralized autologous cancer vaccines prepared from the whole tumor cell lysates of the dissected tumors suppressed the growth of residual tumors, particularly in combination with anti-PD-1 immunotherapy. This study highlights a simple biomineralization approach for the controllable synthesis of cGAS-STING-activating autologous cancer vaccines to suppress postsurgical tumor relapse.
研究领域:
癌症免疫疗法
·
纳米技术
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF IMMUNOLOGY
·
2024
·
IF 3.6
Wang Li,Cao Limin,Li Zhihong,Shao Zhugui,Chen Xia,Huang Zhicheng,He Xiaoxiao,Zheng Junke,Liu Li,Jia Xin-Ming,Xiao Hui
The cyclic GMP-AMP synthase (cGAS)–stimulator of IFN genes (STING) pathway is instrumental to antitumor immunity, yet the underlying molecular and cellular mechanisms are complex and still unfolding. A new paradigm suggests that cancer cells’ cGAS-synthesized cGAMP can be transferred to tumor-infiltrating immune cells, eliciting STING-dependent IFN-β response for antitumor immunity. Nevertheless, how the tumor microenvironment may shape this process remains unclear. In this study, we found that extracellular ATP, an immune regulatory molecule widely present in the tumor microenvironment, can potentiate cGAMP transfer, thereby boosting the STING signaling and IFN-β response in murine macrophages and fibroblasts. Notably, genetic ablation or chemical inhibition of murine volume-regulation anion channel LRRC8/volume-regulated anion channel (VRAC), a recently identified cGAMP transporter, abolished ATP-potentiated cGAMP transfer and STING-dependent IFN-β response, revealing a crucial role of LRRC8/VRAC in the cross-talk of extracellular ATP and cGAMP. Mechanistically, ATP activation of the P2X family receptors triggered Ca2+ influx and K+ efflux, promoting reactive oxygen species production. Moreover, ATP-evoked K+ efflux alleviated the phosphorylation of VRAC’s obligate subunit LRRC8A/SWELL1 on S174. Mutagenesis studies indicated that the phosphorylation of S174 on LRRC8A could act as a checkpoint for VRAC in the steady state and a rheostat of ATP responsiveness. In an MC38-transplanted tumor model, systemically blocking CD39 and ENPP1, hydroxylases of extracellular ATP and cGAMP, respectively, elevated antitumor NK, NKT, and CD8+ T cell responses and restrained tumor growth in mice. Altogether, this study establishes a crucial role of ATP in facilitating LRRC8/VRAC transport cGAMP in the tumor microenvironment and provides new insight into harnessing cGAMP transfer for antitumor immunity.
研究领域:
免疫学
·
癌症生物学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2024
·
IF 13.2
Xitong Ren,Haochen Yao,Jiali Sun,Fuxin Xue,Linjie Cui,Yajun Xu,Kazuo Sakurai,Na Shen,Zhaohui Tang
Immune checkpoint blockade (ICB) therapy represents a promising approach widely embraced for its sustained efficacy upon activation of the body’s immune responses. Nonetheless, its effectiveness exhibits significant variability among patients, with a response rate below 30 %. A key limitation is the insufficient tumor infiltration and specific priming of CD8 + T cells. To address this, we develop ROS-responsive TLR7/8 nanoagonists {methoxy poly(ethylene glycol)- b -poly-[(N-2-hydroxyethyl)-aspartamide]- g -thioketal-R848}, designated as R848 NPs, wherein the C-4 amino of R848 is chemically blocked to enable selective release under endogenous tumor ROS conditions, thereby mitigating the severe systemic cytokine storms associated with R848. Additionally, ultrasound (US) is employed to induce immune cell death and facilitate intratumoral enrichment of R848 NPs. The proposed combination treatment, R848 NPs+US, effectively enhances antigen presentation by dendritic cells (DCs), facilitates intratumoral distribution of active R848, mitigates systemic inflammatory responses, promotes the release of damage-associated molecular patterns, and upregulates the expression of costimulatory molecules on DCs. Ultimately, R848 NPs+US plays a crucial role in bolstering CD8 + T cells immunity, synergizing with αPDL1 for CT26 tumor suppression (rate: 99.0 %, Q value: 1.68), eliciting memory immunity, and preventing tumor rechallenge. This work provides a novel strategy to potentiate the cancer immunity and a guidance for ICB therapy.
研究领域:
癌症免疫疗法
·
纳米技术
·
免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Jingrui Li,Gang Wang,Zhaoyu Wen,Shumin Sun,Zhihui Han,Yuqi Yang,Jie Wu,Zifan Pei,Luyao Liu,Youdong Chen,Liang Cheng
Hydrogen (H 2 ) therapy has demonstrated antitumor effect, but the therapeutic efficacy is restricted by the low solubility and nontarget delivery of H 2 . Electrolysis of H 2 O by electrocatalysts sustainably releases enormous amounts of H 2 and inspires the precise delivery of H 2 for tumor therapy. Herein, manganese-doped Ni 2 S 3 nanoelectrodes (MnNi 2 S 3 NEs) are designed for the electrocatalytic delivery of H 2 and the activation of antitumor immunity to effectively potentiate H 2 -immunotherapy. Ni atoms featuring empty 3d orbitals reduce the initial energy barrier of the hydrogen evolution reaction (HER) by promoting the adsorption of H 2 O. Moreover, Mn atoms with different electronegativity modulate the electronic structure of Ni atoms and facilitate the desorption of the generated H 2 , thus enhancing the HER activity of the MnNi 2 S 3 NEs. Based on the high HER activity, controllable delivery of H 2 for electrocatalytic hydrogen therapy (EHT) is achieved in a voltage-dependent manner. Mechanistically, MnNi 2 S 3 NE-mediated EHT induces mitochondrial dysfunction and oxidative stress, which subsequently activates pyroptosis through the typical ROS/caspase-1/GSDMD signaling pathway. Furthermore, MnNi 2 S 3 NE-mediated EHT enhances the infiltration of CD8 + T lymphocytes into tumors and reverses the immunosuppressive microenvironment. This work demonstrates an electrocatalyst with high HER activity for synergistic gas-immunotherapy, which may spark electrocatalyst-based tumor therapy strategies.
研究领域:
癌症治疗
·
电化学
·
材料科学
·
免疫学
·
生物医学工程
✓ 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）