JOURNAL OF CONTROLLED RELEASE
·
2022
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IF 11.467
Zaigang Zhou,Yu Liu,Wei Song,Xin Jiang,Zaian Deng,Wei Xiong,Jianliang Shen
As a promising cancer treatment, photodynamic therapy (PDT) still achieved limited clinical success due to the severe hypoxia and programmed death ligand-1 (PD-L1) over-expressed immunosuppression tumor microenvironment . At present, few methods have been proven to solve these two defects simply and effectively by a single drug or nano-system simultaneously. To ameliorate this situation, we designed and constructed [email protected] @MnO 2 nanoparticles with two-step oxygen regulation ability and PD-1/PD-L1 axis cascade-disruption capacity via a biomineralization method. In such a nanosystem, manganese dioxide albumin (MnO 2 @Alb) was used as the drug carrier, Butformin (Bu) as mitochondria-associated oxidative phosphorylation (OXPHOS) disruption agent with PD-L1 depression and oxygen reversion ability, and methylene blue (MB) as PDT drug with programmed cell death protein 1 (PD-1) inhibition capacity. Owing to the tumor-responsive capacity of [email protected] @MnO 2 nanoparticles, Bu and MB were selectively delivered and released in tumors. Then, the tumor hypoxia was dramatically reversed by Bu inhibited oxygen consumption, and MnO 2 improved oxygen generation. Following this, the reactive oxygen species (ROS) generation was enhanced by [email protected] @MnO 2 nanoparticles mediated PDT owing to the reversed tumor hypoxia. Furthermore, the immunosuppression microenvironment was also obviously reversed by [email protected] @MnO 2 nanoparticles enhanced immunogenic cell death (ICD) and PD-1/PD-L1 axis cascade-disruption, which then enhanced T cell infiltration and improved its tumor cell killing ability. Finally, the growth of solid tumors was significantly depressed by [email protected] @MnO 2 nanoparticles mediated PDT. All in all, this well-designed nanosystem could solve the defects of traditional PDT via PD-1/PD-L1 axis dual disruption and reversing tumor hypoxia by two-step oxygen regulation.
研究领域:
癌症治疗
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纳米技术
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免疫疗法
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肿瘤学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-22
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IF 12.6
Liu Yanhong,Gong Liming,Feng Jing,Xiao Congcong,Liu Chenfei,Chen Bohan,Chen Liqing,Jin Mingji,Guan Youyan,Gao Zhonggao,Huang Wei
Immune checkpoint inhibition (ICI) has become the mainstay of immunotherapy for the treatment of renal cell carcinoma (RCC). However, only a small portion of patients exhibit a positive response to PD-1/PD-L1 blockade therapy and the key reason is that RCC belongs to a vascular-rich tumor for promoting immunosuppression. Specifically, the dysfunctional tumor vasculature hinders effector T cell infiltration and induces immunosuppressive tumor microenvironment via the release of cytokine, which attenuates the therapeutic efficacy of ICI. Therefore, regulating abnormal tumor vasculature may be a promising strategy to overcome the immunosuppressive microenvironment and enhance ICI therapy. Here, we propose an NGR peptide-modified actively targeted liposome (Axi/siRNA PD−L1 @NGR-Lipo) to encapsulate the anti-angiogenic agents Axitinib and PD-L1 siRNA to promote tumor vasculature normalization and relieve immune evasion for enhanced anti-tumor immunotherapy. With NGR-mediated tumor homing and active targeting, Axi/siRNA PD−L1 @NGR-Lipo could act on tumor vascular endothelial cells to inhibit neo-angiogenesis, increase pericyte coverage and vascular perfusion, and normalize the structure and function of tumor blood vessels. Meanwhile, it also enhanced immune effector T cells and NK cells infiltration and reduced the proportion of immunosuppressive T cells including MDSC cells and Tregs, thus improving the tumor immunosuppressive microenvironment. Moreover, Axi/siRNA PD−L1 @NGR-Lipo reduced the expression of PD-L1 protein in tumor cells, restored the recognition and killing ability of cytotoxic T cells, and relieved immune evasion. As expected, Axi/siRNA PD−L1 @NGR-Lipo displayed superior anti-tumor and anti-metastatic efficacy in mice bearing RCC. Overall, this study demonstrated the important potential of regulating abnormal tumor vasculature to reshape the immunosuppressive microenvironment and boost ICI therapy, which represents a promising avenue for the synergistic anti-tumor with cancer immunotherapy. Graphical
研究领域:
肿瘤学
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免疫学
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药剂学
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产品关联
DOI
PubMed
高影响因子
Nanoscale
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2024
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IF 5.8
Junqiu Liu,Zhaidong Liu,Chunqin Zhao,Yuting Jiao,Baohong Li,Jiaju Shi,Zichao Chen,Zhen Zhang
Exosomal programmed death ligand-1 (ExoPD-L1) is a vital marker of immune activation in the early stages of tumor therapy and it can inhibit anti-tumor immune responses. However, due to the low expression of ExoPD-L1 in cancer cells, it is difficult to perform highly sensitive assays and accurately differentiate cancer sources. Therefore, we constructed a coaxial dual-path electrochemical biosensor for highly accurate identification and detection of ExoPD-L1 from lung cancer based on chemical–biological coaxial nanomaterials and nucleic acid molecular signal amplification strategies. The measurements showed that the detected ExoPD-L1 concentrations ranged from 6 × 102 particles per mL to 6 × 108 particles per mL, and the detection limit was 310 particles per mL. Compared to other sensors, the electrochemical biosensor designed in this study has a lower detection limit and a wider detection range. Furthermore, we also successfully identified lung cancer-derived ExoPD-L1 by analyzing multiple protein biomarkers expressed on exosomes through the “AND” logic strategy. This sensor platform is expected to realize highly sensitive detection and accurate analysis of multiple sources of ExoPD-L1 and provide ideas for the clinical detection of ExoPD-L1.
研究领域:
生物医学工程
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癌症生物学
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电化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Gland Surgery
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2022
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IF 2.16
Meili Zhang,Jialei Gu,Wendong Wang,Kejing Wang,Linfeng Zheng,Jianguo Feng,Jinbiao Shang
Background Identifying the high recurrence group of patients with early-stage papillary thyroid cancer (PTC) is the greatest challenge in the management of this disease. It has been noted that B-type Rafkinase (BRAF) V600E mutation and programmed death ligand 1 (PD-L1) are associated in PTC and highly expressed in PTC, correlating in PTC as potential prognostic biomarkers. However, whether they can be used to predict the aggressiveness and recurrence of early PTC remains unclear. Methods Clinicopathological data of 137 patients with early PTC [tumor-node-metastasis (TNM) stage I–II] who underwent surgery in Zhejiang Cancer Hospital between 2008 and 2010 were retrospectively analyzed. BRAF V600E mutation and PD-L1 was detected by immunohistochemistry. The median follow-up time was 136 months (interquartile range 5.8). The presence of tumor confirmed by imaging or pathology or lymph node metastasis was considered as tumor recurrence. The association of both alone and in combination with clinicopathological features and recurrence was statistically analyzed respectively. The risk of recurrence was assessed using Cox regression models. Results Most of the 137 early PTC were female (78.1%). The mean age was 43.2±12.1 years. The median tumor size was 1.4 cm; 14 patients developed recurrence during follow-up period; 56 patients (40.9%) were detected positive for BRAF V600E mutation; 76 patients (55.5%) were detected positive for PD-L1. Patients with both BRAF V600E mutation and PD-L1 expression had larger tumors (P=0.038), were more likely to have extrathyroidal invasion (P=0.045), and had a lower rate of cervical lymph node metastasis (P=0.046). The recurrence rate was 17.5% (7/40) in patients with BRAF V600E mutation and PD-L1 double expression compared to 8.9% (4/45) in patients with BRAF V600E mutation and PD-L1 double negative [hazard ratio (HR) =1.267; 95% CI: 0.841–1.909; P=0.257]. Survival curves showed flatter recurrence-free survival (RFS) curves in positive BRAF V600E mutation only and PD-L1 expression only, whereas decreased sharply in positive expression of both BRAF V600E mutation and PD-L1; however, the differences were not significant (P>0.05). Conclusions The combination of BRAF V600E mutation and PD-L1 to identify group at higher risk of recurrence in early PTC has insufficient clinical evidence and should be used with caution in the clinical management of PTC.
研究领域:
肿瘤学
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病理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2024
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IF 12.8
Yue Xiong,Chao He,Junyang Qi,Meimei Xiong,Shuna Liu,Jingxin Zhao,Yuzhen Li,Gan Liu,Wenbin Deng
The tumor microenvironment in glioblastoma (GBM) is characterized by a pronounced immunosuppressive state, which significantly hampers tumor treatment and contributes to treatment resistance. While our previous research established that black phosphorus nanosheets (BPNS) inhibited glioblastoma cell migration and invasion, the impact of BPNS on the anti-tumor-associated immune mechanism remains unexplored. This study firstly investigated whether BPNS could modulate the tumor microenvironment through immunotherapy and elucidated the underlying mechanisms. We used a subcutaneous mouse model of GBM, which evaded immune surveillance to evaluate BPNS effects on immune cells within the tumor microenvironment. Our results demonstrated that BPNS significantly enhanced the tumor-suppressive microenvironment, reactivating immune cells' cytotoxicity against tumor cells. Moreover, further analysis revealed that BPNS counteracted the immunosuppressive state by reducing the expression of the immunosuppressive molecule PD-L1 in tumor cells, leading to an anti-tumor effect. Mechanistically, BPNS reduced PD-L1 expression through two main pathways: by inducing autophagy via binding to the HSP90 protein, leading to PD-L1 degradation through the autophagy pathway, and by inhibiting the PI3K-AKT signaling pathway, which reduced PD-L1 mRNA levels. This study expands the understanding of BPNS biological activity and suggests new strategies for utilizing BPNS as an adjuvant in immunotherapy.
研究领域:
肿瘤学
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免疫疗法
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纳米技术
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
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2025
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IF 6.7
Mingli Ye,Lihua Mou,Jianzhou Feng,Lingling Wu,Dangqin Jin,Xiaoya Hu,Qin Xu,Yun Shu
Tumor-derived extracellular vesicles (T-EVs) PD-L1 are an important biomarker for predicting immunotherapy response and can help us understand the mechanism of resistance to immunotherapy. However, this is due to the interference from a large proportion of nontumor-derived EVs. It is still challenging to accurately analyze T-EVs PD-L1 in complex human fluids. Herein, a simple and ultrasensitive method based on the dual-aptamer-proximity ligation assay (PLA)-guided rolling circle amplification (RCA) for the analysis of T-EVs PD-L1 was developed. First, dual aptamers with strong binding affinity were utilized for the recognition of EpCAM and PD-L1 on EVs, and then the aptamer-based PLA occurred. With the aid of the high signal amplification ability of RCA guided by the dual-aptamer-based PLA and efficient magnetic separation, the biosensor could realize highly sensitive quantification of EpCAM and PD-L1 dual-positive EVs with a low detection limit of 7.5 particles/μL. In addition, this method based on the aptamer-PLA-guided RCA was used to discriminate cancer patients from healthy donors with 100% accuracy without additional purification. Overall, this strategy might provide a practical tool for the analysis of multiple proteins on EVs, exhibiting great potential in early cancer diagnosis and treatment.
研究领域:
生物化学
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医学诊断
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cancer Communications
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2025
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IF 24.9
Fanglin Tian,Jian Huang,Weina Fan,Xin Li,Yuning Zhan,Kexin Zhu,Xiangyu Wang,Xin Hong,Xin Wang,Jin Ren,Ying Xing,Li Cai
Background Eps15 homology domain (EHD) proteins, including EHD1 to EHD4, play vital roles in tumor progression. In this study, we aimed to investigate which specific EHD proteins, if any, are implicated in tumor immune evasion and immunotherapy response. Methods The immunotherapy responses of lung adenocarcinoma (LUAD) patients were predicted using tumor immune dysfunction and exclusion (TIDE) analysis. The T cell killing assay was performed by co-culturing activated T cells with LUAD cells. The function of EHD1 as a regulator of programmed death-ligand 1 (PD-L1) endocytic recycling was determined by receptor internalization assays. Methylated RNA immunoprecipitation (MeRIP) was performed to investigate N6-methyladenosine (m 6 A) modification of EHD1 mRNA. The protein-protein interaction was revealed by the molecular docking analysis and validated by immunofluorescence (IF) and immunoprecipitation (IP) assays. RNA immunoprecipitation (RIP) was used to examine the interaction between YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1) and EHD1 mRNA. The regulatory mechanism of YTHDF1 on EHD1 was investigated through the application of m 6 A-binding site mutation analysis. The murine LUAD cells were employed to establish subcutaneous xenograft models within immunocompetent C57BL/6 mice to assess the immunomodulatory impact of EHD1 in vivo. Results TIDE algorithms and survival analysis identified that EHD1 promoted LUAD immune escape. EHD1 knockdown enhanced T cell cytotoxicity in killing LUAD cells across all effector-to-target (E/T) ratios. EHD1 overexpression exerted the opposite effect. The molecular docking analysis revealed an interaction between EHD1 and the PD-L1 protein, verified by IF and IP. Furthermore, EHD1 knockdown inhibited PD-L1 recycling, thereby promoting its lysosomal degradation. Disruption of the EHD1/PD-L1 interaction impaired the regulatory function of EHD1 in tumor immune evasion. In an immune-competent mouse model, we found that EHD1 silencing impeded tumor immune evasion and enhanced the efficacy of anti‑PD‑1 therapy. MeRIP-qPCR confirmed obvious m 6 A modification of EHD1 . Further, the EHD1 mRNA was found to bind to the YTHDF1 protein, an m 6 A reader. YTHDF1 overexpression up-regulated EHD1 expression by enhancing its mRNA stability in an m 6 A-dependent manner. Conclusion Our study illuminates the role of m 6 A-modified EHD1 in tumor immune evasion and immunotherapy responses, thereby offering a novel avenue to potentially enhance immunotherapeutic sensitivity and improve the prognosis for patients with LUAD.
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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生物化学
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RNA生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
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IF 18.5
Wenqian Zhang,Shengming Zhang,Minghao He,Weixian Hu,Wenhao Han,Kangkang Zha,Qian Feng,Guohui Liu,Yanli Zhao,Bobin Mi
Postmenopausal bone loss due to estrogen deficiency necessitates effective therapeutic strategies. Our study explores targeting macrophage Aurora A kinase to mitigate bone loss. Aurora A kinase phosphorylation is observed being increased in bone marrow-derived macrophages (BMDMs) from ovariectomy (OVX) mice, along with a reduction in programmed death-ligand 1 (PD-L1) expression. Detailed analysis reveals that PD-L1 plays an immunomodulatory role by lowering the ratio of T helper 17 cells and regulatory T cells. The metabolic shift toward glycolysis through transcriptome sequencing, induced by Aurora A kinase inhibition, is essential for PD-L1 expression in BMDMs. The interaction between Aurora A kinase and cytochrome C oxidase subunit 5B is found to enhance PD-L1 expression. To apply these findings therapeutically, a multifunctional system is developed using a Nickel-metal organic framework combined with bisphosphonate and MLN8237 (BP@Ni-MOF/MLN8237). This system targets bone tissues through bisphosphonate and effectively delivers MLN8237 to macrophages, promoting PD-L1 expression for a favorable immune environment. Moreover, this system exhibits an obvious angiogenic effect. The present study highlights the crucial roles of macrophage Aurora A kinase and PD-L1 in maintaining bone homeostasis as well as the angiogenesis effect by Ni-MOF engineered system, presenting a promising therapeutic approach to prevent postmenopausal bone loss.
研究领域:
医学
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免疫学
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骨科学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
Journal of Oncology
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2022
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IF 4.501
Junying Xu,Xuejing Yang,Jiadong Pan,Honghong Fan,Jie Mei,Dong Hua
Objective. To investigate the regulatory effect of ZEB1 on PD-L1 expression and the pharmacodynamic effects of Biochanin A on the malignant biological behaviors of colorectal cancer (CRC). Methods. The correlation between epithelial-mesenchymal transition (EMT) score and features of the tumor microenvironment (TME) was investigated using the Cancer Genome Atlas (TCGA) dataset. The correlation between ZEB1 and PD-L1 expression was validated using immunohistochemistry (IHC) staining, and the regulatory effect of ZEB1 on PD-L1 expression was explored by in vitro assays. Moreover, the pharmacodynamic effects of Biochanin A on ZEB1 and PD-L1 expression, as well as malignant biological behaviors of CRC cells, were evaluated by in vitro and in vivo assays. Results. EMT score was positively correlated with a majority of immunostimulators, immune checkpoints, activities of antitumor immunity cycles, and infiltration levels of most immune cells in the TCGA dataset. In addition, ZEB1 was correlated with and positively regulated PD-L1 expression in CRC. Besides, Biochanin A, an inhibitor for the ZEB1/PD-L1 axis, notably inhibited ZEB1-mediated aggressiveness and PD-L1 expression of CRC cells. Moreover, Biochanin A also exerted a tumor-inhibitory role in vivo in the CRC mouse model. Conclusion. Overall, we found that ZEB1 is a main regulator of PD-L1 expression in CRC. In addition, we also identified Biochanin A as a novel inhibitor for the ZEB1/PD-L1 axis, which could inhibit tumor 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
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Microorganisms
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2020
·Vol. 8
·期 2
·175
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IF 4.152
Xuerun Liu,Luoyang Wang,Nan Jing,Guoqiang Jiang,Zheng Liu
Recent advances have revealed the essential role of gut microbiomes in the therapeutic efficiency of immune checkpoint inhibitors (ICIs). Inspired by biostimulation, a method using nutrients to accelerate the growth of soil microorganisms and the recovery of soil microbial consortia, here we propose a bilberry anthocyanin combo containing chitosan and low molecular citrus pectin (LCP), in which LCP–chitosan is used to encapsulate anthocyanins so to enhance its digestive stability and, moreover, modulate the microbiome more favorable for the PD-L1 blockade treatment. Using murine MC38 colon cancer as a model system, we examined the effects of the combo on modulating the gut microbiome and therapeutic efficiency of PD-L1 blockade treatment. It was shown that bilberry anthocyanins enriched the subdominant species, increased both the concentration and the proportion of butyrate in feces and enhanced intratumoral CD8+T cell infiltrations. The application of the bilberry anthocyanin combo restored the species diversity of gut microbiome decreased by LCP–chitosan and achieved the best control of tumor growth. These preliminary results indicated unprecedented opportunities of probiotics combo in improving the therapeutic efficiency of immune checkpoint inhibitor through manipulating gut microbiome.Keywords:immune checkpoint inhibitors;immunotherapy;gut microbiome;bilberry anthocyanins;low molecular citrus pectin;chitosan
研究领域:
免疫疗法
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肿瘤学
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微生物学
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营养保健品
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2023
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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
Cell Death & Disease
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2023
·Vol. 14
·期 2
·1-13
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IF 9
Liu Nian,Zhang Jianglin,Yan Mingjie,Chen Lihui,Wu Jie,Tao Qian,Yan Bei,Chen Xiang,Peng Cong
Patients with advanced melanoma have shown an improved outlook after anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapeutic efficacy remains a major challenge. Here, our findings showed a significantly increased abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanoma tumors via STAT1/3. We also found that supplementation with α-KG significantly increased the activity of the methylcytosine dioxygenases TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 binding to the PD-L1 promoter was stabilized to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, our results provide novel insight into α-KG’s function in anti-PD1 treatment of melanoma and suggest supplementation with α-KG as a novel promising strategy to improve the efficacy of anti-PD1 therapy.
研究领域:
肿瘤学
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免疫学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
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