ACS Applied Materials & Interfaces
·
2024
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IF 8.3
Xin Huang,Jiawei Zhu,Chuhuang Dong,Yuqing Li,Qing Yu,Xuan Wang,Zhejie Chen,Jiabei Li,Yu Yang,Haifang Wang
Ag2S quantum dots (QDs) show superior optical properties in the NIR-II region and display significant clinical potential with favorable biocompatibility. However, inherent defects of low targeting and poor solubility necessitate practical modification methods to achieve the theranostics of Ag2S QDs. Herein, we used rolling circle amplification (RCA) techniques to obtain long single-stranded DNA containing the PD-L1 aptamer and C-rich DNA palindromic sequence. The C-rich DNA palindromic sequences can specifically chelate Ag2+ and thus serve as a template to result in biomimetic mineralization and formation of pApt-Ag2S QDs. These QDs enable specific targeting and illuminate hot tumors with high PD-L1 expression effectively, serving as excellent molecular targeted probes. In addition, due to the high NIR-II absorption of Ag2S QDs, pApt-Ag2S QDs exhibit remarkable photothermal properties. And besides, polyvalent PD-L1 aptamers can recognize PD-L1 protein and effectively block the inhibitory signal of PD-L1 on T cells, enabling efficient theranostics through the synergistic effect of photothermal therapy and immune checkpoint blocking therapy. Summary, we enhance the biological stability and antibleaching ability of Ag2S QDs using long single-stranded DNA as a template, thereby establishing a theranostic platform that specifically targets PD-L1 high-expressing inflamed tumors and demonstrates excellent performance both in vitro and in vivo.
研究领域:
生物医学工程
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肿瘤学
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纳米医学
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2025
·Vol. 44
·期 1
·1-25
·
IF 12.8
Wang Pengyu,Guo Weihua,Liu Shuyue,Li Shouyi,Li Jiaqi,Ding Bowen,Yin Fengyi,Yang Yang,Li Xingjiang,Cao Pei,Ma Chaozhe,Zhang Wanying,Song Yidan,Geng Yating,Liu Lantao,Hu Jing,Hao Jihui,Feng Yukuan
Background Copper accumulation triggers mitochondrial-driven cell death, known as cuproptosis, offering a promising mechanism for targeted cancer therapy. Recent studies have highlighted the critical role of intratumoral copper levels in regulating the expression of programmed cell death ligand-1 (PD-L1), suggesting that copper-induced cuproptosis not only enhances cancer cell death but may also amplify the effects of anti-PD-L1 antibodies (αPD-L1). However, in tumors where monotherapy with αPD-L1 shows limited efficacy, particularly in pancreatic ductal adenocarcinoma (PDAC), the role of copper-induced cuproptosis in enhancing αPD-L1 treatment efficacy and its underlying mechanisms remain unclear. Meanwhile, inadequate tumor drug accumulation and glycolysis significantly restrict the efficacy of cuproptosis. To address these challenges, we have synthesized a novel nanozyme, Pt@PCN-Cu, designed to stabilize intracellular copper accumulation and effectively induce cuproptosis. Additionally, we aim to determine whether this strong induction of cuproptosis can synergize with αPD-L1 to enhance cancer therapy, ultimately paving the way for novel strategies to improve PDAC treatment. Methods Pt@PCN-Cu was synthesized via a one-pot method, and its therapeutic potential was assessed in combination with αPD-L1 for the treatment of PDAC. Initially, the material’s properties were characterized, and its efficient cellular uptake was confirmed. Anti-tumor efficacy was evaluated by inducing cuproptosis in PDAC cell lines and xenograft models. RNA sequencing (RNA-seq) was utilized to identify key regulators involved in the modulation of PD-L1 expression by cuproptosis. Lastly, the therapeutic efficacy of Pt@PCN-Cu combined with αPD-L1 was evaluated in vivo, focusing on tumor growth inhibition and immune modulation within the tumor microenvironment (TME). Results Pt@PCN-Cu demonstrates excellent physicochemical properties and remarkable cascade catalytic activity, providing a solid foundation for further in vitro and in vivo studies. In vitro, Pt@PCN-Cu efficiently transports copper and induces cuproptosis primarily through mitochondrial dysfunction. Mechanistic studies show that Pt@PCN-Cu triggers the dissociation of hexokinase 2 (HK2) from mitochondria, leading to a reduction in HK2 activity. This decline in HK2 activity impairs glycolysis, a metabolic pathway essential for tumor energy metabolism, which in turn results in elevated PD-L1 levels. In vivo, Pt@PCN-Cu demonstrates excellent safety and accumulates at the tumor site in a subcutaneous PDAC mouse model, inducing cuproptosis. Moreover, the combination of Pt@PCN-Cu with αPD-L1 further enhanced its therapeutic efficacy and effectively reprogrammed the immunosuppressive TME. Conclusion This study presents strong evidence confirming the safety and therapeutic potential of Pt@PCN-Cu in PDAC treatment. Importantly, Pt@PCN-Cu not only induces cuproptosis but also significantly enhances antitumor efficacy in combination with αPD-L1 by regulating PD-L1 expression through HK2 modulation. These findings underscore a more effective and innovative approach for treating PDAC.
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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纳米医学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Hang Zhang,Yujie Zhang,Yinping Geng,Xuanlong Zhen,Xiaodi Wang,Qiange Yin,Peng Zhang,Yuanyuan Li,Mengzhen Zhang,Yi-chao Zheng,Bing-rui Liu,Hui-min Liu,Hai-wei Xu
Gastric cancer is one of the major health threats to human beings and has a low response rate to emerging immunotherapy. We herein reported a novel indole-based LSD1-targeted antigastric agent 7ae, which was able to enhance the sensitivity of gastric cancer cells to a T-cell-mediated immune response. It exhibited potent LSD1 inhibitory activity (IC50 = 0.080 ± 0.002 μM) and reduced the expression of PD-L1, which in turn promoted the T-cell killing response in gastric cancer cells. As a result, 7ae acted as an active LSD1 inhibitor, exerting excellent anti-invasion and anti-migration effects in gastric cancer cells and leading to significant suppression of the growth of xenograft gastric tumors without obvious toxicity in vivo. Collectively, 7ae has been demonstrated to be a novel, potent LSD1 inhibitor with the potential to be used as an antigastric agent, as well as a useful tool compound for exploratory studies of T-cell-mediated immunity and/or immunotherapy in gastric cancer.
研究领域:
肿瘤学
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药理学
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免疫学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Yu Chen,Jie Mei,Ping Zhang,Jiayu Liu,Lingyan Chen,Liwei Wu,Yan Zhang
IQ motif containing GTPase activating protein 1 (IQGAP1) is a scaffold protein to transduce multiple signals from the extracellular microenvironment. However, whether IQGAP1 mediates EGF-induced cancer progression has been not observed. In this research, we explored the immunological correlations of IQGAP1. IQGAP1 was up-regulated in most cancer and related to poor prognosis in ovarian cancer. In addition, IQGAP1 was correlated with immune-related genes and tumor-infiltrating lymphocytes. IQGAP1 was a novel EGF-response gene, which was up-regulated by EGF. As the downstream of EGFR, IQGAP1 mediated EGF-induced proliferation, migration and invasion of tumor cells and was essential for EGF-induced PD-L1 expression as well. Mechanically, IQGAP1 interacted with STATs and mediated their phosphorylation. Furthermore, Curcumin inhibited EGFR/IQGAP1 axis to down-regulate PD-L1 and suppress cancer progression. To sum up, IQGAP1 responds to EGF stimulation and mediates EGF-induced phosphorylation of STATs, which is a novel promising target for blocking the EGF-induced cancer progression.
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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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2021
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IF 5.275
Gaochao Lv,Yinxing Miao,Yinfei Chen,Chunmei Lu,Xiuting Wang,Minhao Xie,Ling Qiu,Jianguo Lin
Programmed death ligand 1 (PD-L1) expression level is a reproducible biomarker for guiding stratification of patients to immunotherapy. However, the most widely used immunohistochemistry method is incompetent to fully understand the PD-L1 expression level in the whole body because of the highly complex PD-L1 expression in the tumor microenvironment. In this work, a novel small-molecular radiotracer [ 18 F]LG-1 based on the biphenyl active structure was developed to evaluate PD-L1 expression in tumors. [ 18 F]LG-1 was obtained by conjugating and radiolabeling with [ 18 F]FDG with high radiochemical purity (>98.0%) and high molar activity (37.2 ± 2.9 MBq/nmol). In vitro experimental results showed that [ 18 F]LG-1 could target PD-L1 in tumor cells and the cellular uptake in A375-hPD-L1 cells (PD-L1 + ) was clearly higher than that in A375 cells (PD-L1-). In vivo dynamic PET images of [ 18 F]LG-1 provided clear visualization of A375-hPD-L1 tumor with high tumor-to-background contrast, and the tumor uptake was determined to be 3.98 ± 0.21 %ID/g at 60 min, which was 2.6-fold higher than that of A375 tumor. These results suggested that [ 18 F]LG-1 had great potential as a promising PD-L1 radiotracer.
研究领域:
医学影像学
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肿瘤学
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核医学
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DOI
PubMed
高影响因子
NEOPLASIA
·
2021
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IF 5.715
Yihui Ma,Peiyi Xia,Zhengyang Wang,Jingjing Xu,Lan Zhang,Yanan Jiang
Protein Disulfide Isomerase Family A Member 6 (PDIA6) is an endoplasmic reticulum protein that is capable of catalyzing protein folding and disulfide bond formation. Abnormally elevated expression of PDIA6 has been reported to predict poor outcomes in various cancers. Herein, gain-of- and loss-of-function experiments were performed to investigate how PDIA6 participated in the carcinogenesis of pancreatic cancer (PC). By analyzing the protein expression of PDIA6 in 28 paired PC and para carcinoma specimens, we first found that PDIA6 expression was higher in PC samples. Both the overall survival and disease-free survival rates of PC patients with higher PDIA6 expression were poorer than those with lower PDIA6 ( n = 178). Furthermore, knockdown of PDIA6 impaired the malignancies of PC cells — suppressed cell proliferation, invasion, migration, cisplatin resistance, and xenografted tumor growth. PDIA6-silenced PC cells were more sensitive to cytotoxic natural killer (NK) cells. Overexpression of PDIA6 had opposite effects on PC cells. Interestingly, COP9 signalosome subunit 5 (CSN5), a regulator of E3 ubiquitin ligases known to promote deubiquitination of its downstream targets, was demonstrated to interact with PDIA6, and its expression was increased in PC cells overexpressing PDIA6. Additionally, PDIA6 overexpression promoted deubiquitination of β-catenin and PD-L1 and subsequently upregulated their expression in PC cells. These alterations were partly reversed by CSN5 shRNA. Collectively, the above results demonstrate that PDIA6 contributes to PC progression, which may be associated with CSN5-regulated deubiquitination of β-catenin and PD-L1. Our findings suggest PDIA6 as a potential target for the treatment of PC.
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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癌症生物学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·Vol. 12
·期 17
·2300110
·
IF 10
Shuaiying Wu,Jianzhong Zhang,Jie Pan,Shuang Bai,Ziying Wang,Yulun Chen,Dazhuang Xu,Yibo An,Chao Liu,Chengchao Chu,Qixuan Dai,Lai Jiang,Zhixiang Lu,Gang Liu
It is an engaging program for tumor treatment that rationalizes the specific microenvironments, activation of suppressed immune system (immune resistance/escape reversion), and synergistic target therapy. Herein, a biomimetic nanoplatform that combines oxidative stress with genetic immunotherapy to strengthen the therapeutic efficacy is developed. Ru-TePt nanorods, small interfering RNA (PD-L1 siRNA), and biomimetic cellular membrane vesicles with the targeting ability to design a multifunctional Ru-TePt@siRNA-MVs system are rationally integrated. Notably, the Fenton-like activity significantly enhances Ru-TePt nanorods sonosensitization, thus provoking stronger oxidative stress to kill cells directly. Meanwhile, immunogenic cell death is triggered to secrete numerous cytokines and activate T cells. The effective catalase characteristics of Ru-TePt enable the in situ oxygen-producing pump to improve tumor oxygen level and coordinately strengthen the therapeutic effect of SDT followed. More importantly, anti-PD-L1-siRNA mediated immune checkpoint silence of the PD-L1 gene creates an environment conducive to activating cytotoxic T lymphocytes, synergistic with boosted reactive oxygen species-triggered antitumor immune response. The experimental results in vitro and in vivo reveal that the Ru-TePt@siRNA-MVs nanosystems can effectively activate the oxidative stress-triggered immune response and inhibit PD-1/PD-L1 axis-mediated immune resistance. Consequently, this orchestrated treatment paradigm provides valuable insights for developing potential oxidative stress and genetic immunotherapy.
研究领域:
肿瘤学
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纳米技术
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免疫治疗
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分子生物学
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生物医学工程
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PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Zekun Zeng,Zhiwei Yang,Chenghao Li,Shujing Liu,Wei Wei,Ye Zhou,Simeng Wang,Mengjun Sui,Mengdan Li,Shumei Lin,Yangyang Cheng,Peng Hou
Despite the considerable achievements of antibodies targeting PD-1/PD-L1 in cancer immunotherapy, limitations in antitumor immune response and pharmacokinetics hinder their clinical adoption. Small molecules toward PD-L1 degradation signifies an innovative avenue to modulate PD-1/PD-L1 axis. Herein, we unveil a comprehensive engineering involving the development of new PD-L1 degraders based on the berberine (BBR) and palmatine (PMT) bioactive frameworks and explore their translational potential for cancer immunotherapy using a peptide-drug conjugate strategy. Chemical modifications at the O-9 position of PMT dramatically enhance the PD-L1 degradation capacity. Further conjugation of PMT degraders with an anti-PD-L1 peptide featuring disulfide linkers enables efficient GSH-specific prodrug activation, yielding synergistic immunotherapeutic benefits through both external PD-L1 blockade and internal PD-L1 degradation mechanisms. This work elucidates the compelling charm of the discovery and application of PD-L1 degraders, offering solutions to the challenges in advancing cancer immunotherapy in widespread clinics.
研究领域:
肿瘤学
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免疫学
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药学
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分子生物学
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2020
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IF 10.652
Ningning Wang,Yaxin Zhou,Yuwen Xu,Xiaomeng Ren,Shiyao Zhou,Qi Shang,Yue Jiang,Yuxia Luan
Immune checkpoint blockade (ICB) strategy based on suppressing programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has been proved to be promising and effective in cancer immunotherapy. However, its potential risk of immune-related adverse events (irAEs) places stringent requirements on the precise loading of anti-PD-L1 agent in nanomedicine. Precise control of the loading content of anti-PD-L1 antibody is a difficult task since physical encapsulation has inevitable drawbacks like batch-to-bath variation and chemical modification is limited by the low stability of the antibody. Herein, we proposed a molecular engineering strategy to develop the nanomedicine with precise control of anti-PD-L1 agent content by using anti-PD-L1 peptide (APP) as the substitute to anti-PD-L1 antibody. The APP was chemically bonded with a photosensitizer IR780 to obtain IR780-M-APP, a molecule able to self-assemble into nanoparticles (NPs) with a precise APP loading (48.4 wt%) determined by the molecular structure. Specifically, the IR780 moiety in IR780-M-APP NPs endows the nanoparticles with photodynamic therapeutic effect as well as the ability to trigger immunogenic cell death (ICD), while the APP moiety can block the PD-1/PD-L1 pathway for promoting immunotherapy. The proposed photodynamic-immunotherapy nanoplatform not only killed primary tumors directly but also eradicated the metastatic and invasive tumors effectively. The present molecular engineering strategy combined with anti-PD-L1 peptide might provide more opportunities for the design of advanced nanoplatforms for cancer therapy.
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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分子工程
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DOI
高影响因子
Acta Pharmaceutica Sinica B
·
2024
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IF 14.7
Jiaojiao Yu,Yujin Xiang,Yuzhen Gao,Shan Chang,Ren Kong,Xiaoxi Lv,Jinmei Yu,Yunjie Jin,Chenxi Li,Yiran Ma,Zhenhe Wang,Jichao Zhou,Hongyu Yuan,Shuang Shang,Fang Hua,Xiaowei Zhang,Bing Cui,Pingping Li
Protein kinase C α (PKC α ) regulates diverse biological functions of cancer cells and is a promising therapeutic target. However, clinical trials of PKC-targeted therapies have not yielded satisfactory results. Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms. In this study, we found that PKC α inhibition enhances CD8 + T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice. We further identified PKC α as a critical regulator of programmed cell death-ligand 1 (PD-L1) and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression. We demonstrated that PKC α -mediated PD-L1 phosphorylation promotes PD-L1 degradation through β transducin repeat-containing protein. Notably, the efficacy of PKC α inhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo . Clinical tissue array analysis revealed that PKC α expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKC α , identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies, and provided a proof of concept for targeting PKC α in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC.
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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癌症治疗
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-18
·
IF 10.435
Zhao Bonan,Dong Zhipeng,Liu Weixing,Lou Fangning,Wang Qiyan,Hong Hao,Wang Yue
Background According to data estimated by the WHO, primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of death around the world. Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, so effective therapy is highly desired for HCC. Results In this study, the use of poly( l -Aspartic acid)-poly(ethylene glycol)/combretastatin A4 (CA4-NPs) was aimed to significantly disrupt new blood vessels in tumor tissues for targeted hepatic tumor therapy. Here, PEG-b-PAsp-g-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, CA4-NPs were mainly distributed at the tumor site because of the triple target effects—enhanced permeability and retention (EPR) effect, acid-sensitive (pH = 5.5) effect to the tumor microenvironment (TME), and good selectivity of CA4 for central tumor blood vessel. Considering that CA4-NPs might induce severe hypoxic conditions resulting in high expression of HIF-1α in tumor tissues, which could induce the overexpression of PD-L1, herein we also used a programmed death-ligand 1 antibody (aPD-L1) to prevent immunosuppression. This way of complementary combination is able to achieve an ideal treatment effect in tumor site where CA4-NPs and aPD-L1 could respond to the inner area and peripheral area, respectively. As a result, a significant decrease in tumor volume and weight was observed in the combination group of CA4-NPs plus aPD-L1 compared with CA4-NPs or aPD-L1 monotherapy in subcutaneous Hepa1-6 hepatic tumor models. Conclusions We presented a new idea that co-administration of CA4-NPs and aPD-L1 possessed notable anti-tumor efficacy for HCC treatment. Graphic abstract
研究领域:
肿瘤学
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药学
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免疫疗法
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PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Wei Xiong,Lin Qi,Ning Jiang,Qi Zhao,Lingxiao Chen,Xin Jiang,Yuan Li,Zaigang Zhou,Jianliang Shen
Photodynamic therapy (PDT) is a promising strategy for cancer treatment. It can not only generate reactive oxygen species (ROS) to cause the chemical damage of tumor cells in the presence of enough oxygen but also promote the antitumor immunity of T cells through enhancing the production of interferon γ (IFN-γ). However, one phenomenon is ignored so far that the enhanced production of IFN-γ caused by PDT may significantly increase the expression of programmed death-ligand 1 (PD-L1) on the tumor cell membrane and thus could inhibit the immune killing effects of T cells. Herein, we report the construction of a composite by loading metformin (Met) and IR775 into a clinically usable liposome as a two-in-one nanoplatform (IR775@Met@Lip) to solve this problem. The IR775@Met@Lip could reverse tumor hypoxia to enhance ROS production to elicit more chemical damage. Besides, the overexpression of PD-L1 by PDT was also effectively down-regulated. These therapeutic benefits including decreased PD-L1 expression, alleviated T cell exhaustion, and reversed tumor hypoxia successfully suppressed both the primary and abscopal tumor growth in bladder and colon cancers, respectively. Combining with its excellent biocompatibility, our results indicate that this IR775@Met@Lip system has great potential to become a highly effective cancer therapy modality.
研究领域:
癌症研究
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药学
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免疫治疗
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纳米技术
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生物医学工程
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DOI
PubMed
高影响因子
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