Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Yuanyuan Zhang,Weiwei Jin,Zhichao Deng,Bowen Gao,Yuanyuan Zhu,Junlong Fu,Chenxi Xu,Wenlong Wang,Ting Bai,Lianying Jiao,Hao Wu,Mingxin Zhang,Mingzhen Zhang
Sonodynamic therapy (SDT) can potentially induce immunogenic cell death in tumor cells, leading to the release of ATP, and facilitating the initiation of an immune response. Nevertheless, the enzymes CD39 and CD73 can swiftly convert ATP into immunosuppressive adenosine (ADO), resulting in an immunosuppressive tumor microenvironment (TME). This study introduced a nanomedicine (QD/POM1@NP@M) engineered to reprogram TME by modulating the CD39/CD73/ADO pathway. The nanomedicine encapsulated sonosensitizers silver sulfide quantum dots, and the CD39 inhibitor POM1, while also incorporating homologous tumor cell membranes to enhance targeting capabilities. This integrated approach, on the one hand, stimulates the release of ATP via SDT, thereby initiating the immune response. In addition, it reduced the accumulation of ADO by inhibiting CD39 activity, which ameliorated the immunosuppressive TME. Upon administration, the nanomedicine demonstrated substantial anti-tumor efficacy by facilitating the infiltration of anti-tumor immune cells, while reducing the immunosuppressive cells. This modulation effectively transformed the TME from an immunologically “cold” state to a “hot” state. Furthermore, combined with the checkpoint inhibitor α -PDL1, the nanomedicine augmented systemic anti-tumor immunity and promoted the establishment of long-term immune memory. This study provides an innovative strategy for combining non-invasive SDT and ATP-driven immunotherapy, offering new ideas for future cancer treatment.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2024
·
IF 4.6
Xiong Zhonghua,Deng Jiahui,Xie Pandeng,Tang Chongyang,Wang Jing,Deng Qinqin,Yang Yujiao,Zhang Jing,Guo Mengyi,Wang Xiongfei,Guan Yuguang,Luan Guoming,Zhou Jian,Li Tianfu
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus is an efficacious treatment option for patients with refractory epilepsy. Our previous study demonstrates that adenosine is a potential target of DBS for the treatment of epilepsy. Equilibrative nucleoside transporters-1 (ENT1) and ectonucleotidases (CD39, CD73) function as regulators of extracellular adenosine in the brain. It is unclear whether ENT1, CD39, and CD73 are involved in the mechanism of DBS for epilepsy. A total of 48 SD male rats were divided into four groups: control (naïve rats), Pilo (pilocarpine induced rats with epilepsy), DBS (rats with epilepsy treated with DBS for 8 weeks), and sham. In the present study, video electroencephalogram monitoring, Morris water maze assays, in vivo measurements of adenosine using fiber photometry, histochemistry, and western blot were performed on the hippocampus. DBS markedly attenuated spontaneous recurrent seizures (SRSs) and enhanced spatial learning in rats with epilepsy, assessed through video-EEG and water maze assays. Fibred photometry measurements of an adenosine sensor revealed dynamic increase in extracellular adenosine during DBS. The expressions of ENT1, CD39, and CD73 in Pilo group and sham group increased compared with the control group, while the expressions of ENT1, CD39, and CD73 in DBS group decreased compared to that of Pilo group and sham group. The findings indicate that DBS reduces the number of SRSs and improves spatial memory in rats with epilepsy with concomitant decrease of ENT1, CD39, and CD73 expressions. Adenosine-modulating enzymes might be the potential targets of DBS for the treatment of epilepsy.
研究领域:
神经科学
·
药理学
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癫痫学
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神经病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-20
·
IF 10.6
Li Tan,Zhang Xingyu,Shi Chengyu,Liu Qiao,Zhao Yuetao
Combination of tumor immunotherapy with photothermal therapy (PTT) is a feasible tactic to overcome the drawback of immunotherapy such as poor immune response. Via triggering the immunogenic cells death (ICD), PTT can stimulate the activity of immune cells, but meanwhile, the level of adenosine is elevated via the CD73-induced decomposition of ATP which is overexpressed accompanying with the PTT process, resulting in negative feedback to impair the immune stimulation. Herein, we developed a novel biomimetic photothermal nanodrug to specifically block CD73 for inhibition of adenosine production and more efficient priming of the suppressive immune microenvironments. The nanodrug, named as AptEM@CBA, is constructed by encapsulation of photothermal agent black phosphorus quantum dots (BPQDs) and selective CD73 inhibitor α, β-Methyleneadenosine 5′-diphosphate (AMPCP) in chitosan nanogels, which are further covered with aptamer AS1411 modified erythrocyte membrane (EM) for biomimetic camouflage. With AS1411 induced active targeting and EM induced long blood circulation time, the enrichment of the nanodrug tumor sites is promoted. The photothermal treatment promotes the maturation of dendritic cells. Meanwhile, the release of AMPCP suppress the adenosine generation via CD73 blockade, alleviating the impairment of adenosine to dendritic cells and suppressing regulatory T cells, synergically stimulate the activity of T cells. The combination of CD73 blockade with PTT, not only suppresses the growth of primary implanted tumors, but also boosts strong antitumor immunity to inhibit the growth of distal tumors, providing good potential for tumor photoimmunotherapy.
研究领域:
纳米技术
·
癌症免疫治疗
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光热疗法
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药物递送系统
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Hao Zhang,Li Yang,Mengxiao Han,Yaobao Han,Zhilin Jiang,Qing Zheng,Jun Dong,Tingting Wang,Zhen Li
The currently available immune checkpoint therapy shows a disappointing therapeutic efficacy for glioblastoma multiforme (GBM), and it is of great importance to discover better immune checkpoints and develop innovative targeting strategies. The discovered metabolic immune checkpoint ecto-5-nucleotidase (CD73) in a tumor contributes to its immune evasion due to the dysregulation of extracellular adenosine (ADO), which significantly inhibits the function of antitumor T cells and increases the activity of immunosuppressive cells. Herein, we drastically inhibit the expression of CD73 to reduce the production of ADO by using versatile Au@Cu2–xSe nanoparticles (ACS NPs). ACS NPs can decrease the expression of CD73 by alleviating the tumor hypoxia through their Fenton-like reaction to weaken the ADO-driven immunosuppression for enhancing antitumor T cell infiltration and activity of GBM. The copper ions (Cu2+) released from ACS NPs can chelate with disulfide, leading to the formation of cytotoxic bis(N,N-diethyldithiocarbamate)-copper complex (CuET), which can be combined with radiotherapy to recruit more antitumor T cells to infiltrate into the tumor site. Based on the inhibition of CD73 to promote the infiltration and activity of antitumor T cells, a cascade of enhancing GBM immunotherapy effects can be achieved. The significant increase in CD8+ T and CD4+ T cells within the tumor and the memory T cells in the spleen effectively reduces tumor size by 92%, which demonstrates the excellent efficacy of immunotherapy achieved by a combination of metabolic immune checkpoint CD73 inhibition with chemoradiotherapy. This work demonstrates that modulation of CD73-mediated tumor immunosuppression is an important strategy of improving the outcome of GBM immunotherapy.
研究领域:
肿瘤学
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免疫治疗
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纳米技术
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癌症研究
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产品关联
DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2026
·
IF 13.6
Tang Tianyu,Yang Wuping,Lu Minghao,Peng Ding,Li Shiqi,Cui Sijia,Ye Sunyi,Liu Jiandong,Wang Yifan,Wu Cunjin,Teng Haoyang,Huang Haojie,Xu Xin,Xia Dan,Zhu Yi
Aberrant tumor metabolism plays a crucial role in establishing and sustaining an immunosuppressive microenvironment. CD73, a key enzyme in the purine metabolism pathway, is frequently overexpressed in tumors, leading to elevated extracellular adenosine (ADO) levels. This accumulation suppresses antitumor immune responses by promoting immune cell exhaustion, ultimately contributing to immunotherapy resistance. However, the mechanisms underlying CD73 upregulation in tumors remain poorly defined. Here, we identify aurora kinase B (AURKB) as a critical regulator of CD73 overexpression in renal cell carcinoma (RCC), orchestrating immune evasion and resistance to immune checkpoint therapy. AURKB is highly expressed in RCC, with its prognostic significance being especially evident in tumors with strong immunogenicity. Mechanistically, AURKB enhances CD73 expression, thereby promoting T cell dysfunction and immune suppression. Mass cytometry (CyTOF) analysis revealed that AURKB inhibition facilitates immune infiltration and alleviates immune exhaustion. We further demonstrate that AURKB directly interacts with CD73 and phosphorylates it at serine 429, which inhibits STUB1-mediated ubiquitination and proteasomal degradation of CD73. Targeting AURKB to modulate the post-translational stability of CD73 restores antitumor immunity and synergizes with immune checkpoint blockade in vivo. Collectively, this study uncovers a previously unrecognized AURKB–CD73 axis and provides a mechanistically informed strategy to enhance immunotherapy efficacy in RCC.
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产品关联
DOI
高影响因子
ACS Applied Nano Materials
·
2025
·
IF 5.5
Jian Guo,Wen-Ping Lin,Tao Tang,Fushou Liu,Fangtao Tan,Longshua Qin,Wendi Xu,Hao Li,Zhi-Jun Sun,Ran Cui,Mingxi Zhang
The immunosuppressive tumor microenvironment (TME), characterized by elevated adenosine levels, poses a significant barrier to effective cancer immunotherapy. Herein, we report an ultrasound-activatable nanoprobe based on piezoelectric quantum dots (QDs) emitting in the near-infrared-IIb (NIR-IIb) window. The nanoprobe integrates a fluorescent QDs core with tumor-targeting peptides and CD73 inhibitors conjugated via a reactive oxygen species (ROS)-responsive linker. Attributed to the optimized piezoelectricity of the QDs core, this nanoprobe could generate ROS under deep-penetrating ultrasound irradiation. The bright NIR-IIb fluorescence and tumor-targeting ability enable the noninvasive delineation of the tumor margin from normal tissue, guiding the optimal scope and timing of ultrasound treatment. The precise ultrasound irradiation triggers the cleavage of the ROS-responsive linker and the release of the CD73 inhibitor, which effectively inhibits the production of adenosine in TME. This reduction alleviates immunosuppression and robustly activates antitumor immunity in mice, achieving significant therapeutic efficacy. This work provides a promising strategy for overcoming adenosine-mediated immunosuppression and advancing precise ultrasound therapy for cancers.
研究领域:
肿瘤学
·
医学影像
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免疫治疗
·
生物材料
✓ 已验证
产品关联
DOI
高影响因子
Science Advances
·
2026
·Vol. 12
·期 20
·
IF 13.9
Xuhong Yang,Hui Yang,Nuo Xu,Yini Zhu,Zhengcheng Yun,Haoge Zhang,Jia Miao,Yinzhuo Xie,Lin Gao,Leqian Ying,Lei Dong,Yuqi Wang,Yicheng Ni,Jinbing Xie
Immune checkpoint inhibitors show promise in the treatment of melanoma brain metastases but are limited by CD73/adenosine axis-mediated immune evasion. Directly targeting CD73 with antibodies faces challenges due to poor blood-brain barrier permeability and metabolic regulators within the tumor microenvironment (IL-17-driven HIF-1α/VEGF-A). To overcome these barriers, we developed a nose-to-brain delivery platform using glycerol as a mucosal penetration enhancer to codeliver anti–IL-17 and anti-CD73 antibodies. Glycerol reversibly opened nasal epithelial tight junction proteins, enhancing the brain delivery of anti–IL-17 and anti-CD73 antibodies by 19.4- and 17.1-fold, respectively, while minimizing systemic exposure. Critically, anti–IL-17 attenuated CD73/adenosine axis-mediated immune evasion, significantly boosting anti-CD73 targeting efficacy. Ultimately, this combination promoted CD8 + T cell activation and residency, pro-inflammatory macrophage polarization, and reduced T reg cell infiltration, thereby eliciting a strong antitumor effect. Our results establish an efficient nose-to-brain delivery platform for macromolecules and propose a therapeutic strategy for tumors using anti–IL-17 to overcome TME-imposed limitations in CD73-targeted immunotherapy.
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Tingting Wu,Lulu Wang,Chen Jian,Chen Gao,Yajing Liu,Zhiwen Fu,Chen Shi
Refractory fracture presents an intractable challenge in trauma treatment. Selective polarization of macrophages as well as the recruitment of osteogenic precursor cells play key roles in osteogenic differentiation during fracture healing. Here we constructed regulatory T cell (Treg)-derived exosomes (Treg-Exo) for the treatment of fracture. The obtained exosomes displayed a spheroid shape with a hydrated particle size of approximately 130 nm. With further purification using CD39 and CD73 antibody-modified microfluidic chips, CD39 and CD73 specifically expressing exosomes were obtained. This kind of Treg-Exo utilized the ectonucleotidases of CD39 and CD73 to catalyze the high level of ATP in the fracture area into adenosine. The generated adenosine further promoted the selective polarization of macrophages. When interacting with mesenchymal stem cells (MSCs, osteogenic precursor cells), both Treg-Exo and Treg-Exo primed macrophages facilitated the proliferation and differentiation of MSCs. After administration in vivo , Treg-Exo effectively promoted fracture healing compared with conventional T cell-derived exosome. To further improve the delivery efficacy of exosomes and integrate multiple biological processes of fracture healing, an injectable hydrogel was fabricated to co-deliver Treg-Exo and stromal cell-derived factor 1 alpha (SDF-1α). With the dual effect of Treg-Exo for macrophage polarization and SDF-1α for MSC recruitment, the multifunctional hydrogel exerted a synergistic effect on fracture repair acceleration. This study provided a promising therapeutic candidate and synergistic strategy for the clinical treatment of fracture.
研究领域:
免疫学
·
再生医学
·
骨科
·
细胞生物学
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Yihang Gong,Yusheng Cheng,Fanxin Zeng,Xiaoquan Liu,Yang Yang,Feng Zhang,Chaoyao Wen,Fan Yang,Hua Li,Yizhan He,Beibei Ni,Yan Xu,Lan Xiao,Qi Zhang,Lei Zhou,Jun Zheng,Wenjie Chen
Liver resection represents a main curative treatment for patients with early-stage hepatocellular carcinoma (HCC), but there is a rather high incidence of postoperative HCC relapse, which severely shortens long-term survival time. Currently, no standard adjuvant strategies are available for preventing HCC relapse in clinical practice. Impaired natural killer (NK) cell anti-tumor immunity has been disclosed as a crucial root of HCC relapse, indicating that reinstating NK cell anti-tumor immunity may show promise to curb HCC relapse. Coincidently, mounting evidence shows that radiotherapy (RT) can trigger NK cell anti-tumor immunity, though its mechanisms have never been completely elucidated. Herein, we uncover that RT can induce immunogenic cell death and activate cGAS-STING pathway in HCC cells to elicit NK cell anti-tumor immunity. However, RT is also revealed to enhance autophagy and CD73 expression in HCC cells, as well as neutrophil extracellular traps (NETs) formation, which largely limits RT-induced activation of NK cell anti-tumor immunity. Therefore, a cocktail of autophagy inhibitor 3-methyladenine, CD73 inhibitor ARL 67156 trisodium and NETs lyase DNase I may sensitize RT to reinvigorate NK cell anti-tumor immunity and thus prevent HCC relapse postresection. To minimize therapy-related side effects, a nanocomposite powder encapsulating such a triple-drug cocktail is developed. This powder can rapidly form adhesive hydrogel in situ after applied to surgical margin, consequently fulfilling liver-localized sustained drug delivery. Importantly, it can sensitize RT to reinstate NK cell anti-tumor immunity to combat postoperative HCC relapse in Heap1-6-HCC murine model. Besides, this powder can also generate rapid hemostasis in rat and porcine models. Altogether, this work provides an innovative strategy to thwart postoperative HCC relapse and bleeding.
研究领域:
肿瘤学
·
免疫学
·
药剂学
✓ 已验证
DOI
高影响因子
ACS Applied Bio Materials
·
2025
·
IF 4.7
Haizhu Shi,Qian Chen,Shuling Yang,Chungu Zhang,Yu Wan,Shun Feng,Lian-Hai Shan
Mesoporous silica nanoparticles (MSNs) are promising drug carriers for cancer therapy, yet their clinical utility is hampered by premature drug leakage and poor tumor specificity. To address these challenges, we developed a molecularly imprinted polymer (MIP)-gated nanoplatform (mMSN/DOX-MIP) using a CD73 epitope peptide (WELTILHTN) as a template. The ultrathin MIP shell (<1 nm), synthesized from N,N′-bis(acryloyl) cystamine and dimethylaminoethyl methacrylate, functions both as a biomimetic antibody for specific tumor targeting and as a stimuli-responsive gatekeeper. Under physiological conditions (pH 7.4), the MIP layer remains stable, restricting doxorubicin (DOX) leakage to <7% over 96 h. Conversely, in the tumor microenvironment (TME, 10 mM glutathione, pH 5.5), rapid degradation of the MIP shell triggers >90% DOX release within 48 h. In vitro studies demonstrate selective targeting of CD73-overexpressing 4T1 cells, with 4.5-fold higher cellular uptake compared to that of CD73-low TC-1 cells. In vivo evaluations in 4T1 tumor-bearing mice reveal prolonged circulation, enhanced tumor accumulation, and potent therapeutic efficacy, achieving 90% tumor growth inhibition with minimal systemic toxicity. The epitope imprinting further improves the tumor penetration and specificity. This work not only validates the dual functionality of MIP-gated MSNs in precise drug delivery but also highlights their translational potential for treating CD73-high malignancies by synergizing tumor-targeted recognition with TME-triggered release mechanisms.
研究领域:
纳米技术
·
药物输送
·
癌症治疗
·
材料科学
·
生物工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Zexin Yang,Kang Liu,Huihui Li,Yunlong Li,Quanwei Sun,Wencui Shang,Mingjing Wang,Ye Yang,Hanmeng Liu,Dengke Yin,Wei Shen
Although traditional immunogenic cell death (ICD) inducers generate in situ vaccines (ISV) to potentiate antiprogrammed cell death ligand 1 (anti-PDL1) antibodies therapy, their efficacy remains limited. This limitation may be attributed to the physical barrier created by extracellular matrix (ECM) and immunosuppressive metabolic barrier mediated by adenosine. Here, we report an oncolytic polymer (OP), a well-designed ε-polylysine derivative with ICD-inducing capacity, which can simultaneously facilitate the release of endogenous ECM-degrading enzyme, Cathepsin B. The OP alone is sufficient to induce ISV within tumors and disrupt physical barriers without the need for any additional ECM-regulatory drugs. Furthermore, an oncolytic hydrogel codelivering OP and CD73 inhibitor (AMPCP) was developed (OP@AMPCP Gel). Intratumoral injection of OP@AMPCP Gel generates ISV, decreases tumor ECM deposition, enhances antigen delivery to lymph nodes, increases immune cell infiltration, and promotes penetration of anti-PDL1 antibodies, while reducing adenosine levels. OP@AMPCP Gel+anti-PDL1 treatment showed better therapeutic efficacy than oxaliplatin + anti-PDL1 group against breast cancer. Moreover, 80% of melanoma-bearing mice showed complete tumor regressions after receiving OP@AMPCP Gel + anti-PDL1 treatment. Impressively, OP@AMPCP Gel + anti-PDL1-treated mice showed resistance to tumor rechallenge and metastasis, suggesting induction of long-lasting systemic antitumor immunity. Overall, this study presents an oncolytic hydrogel capable of inducing ISV and remodeling the tumor physical barrier and immunosuppressive barrier, offering a promising strategy for customizing personalized immunotherapy.
研究领域:
癌症免疫治疗
·
生物材料
·
肿瘤生物学
·
药物递送
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）