Signal Transduction and Targeted Therapy
·
2024
·Vol. 9
·期 1
·1-15
·
IF 40.8
Wang Chunling,Xu Junchao,Cheng Xiaoyu,Sun Ge,Li Fenfen,Nie Guangjun,Zhang Yinlong
The inadequate tumor accumulation of anti-cancer agents is a major shortcoming of current therapeutic drugs and remains an even more significant concern in the clinical prospects for nanomedicines. Various strategies aiming at regulating the intratumoral permeability of therapeutic drugs have been explored in preclinical studies, with a primary focus on vascular regulation and stromal reduction. However, these methods may trigger or facilitate tumor metastasis as a tradeoff. Therefore, there is an urgent need for innovative strategies that boost intratumoral drug accumulation without compromising treatment outcomes. As another important factor affecting drug tumor accumulation besides vasculature and stroma, the impact of tumor-associated lymphatic vessels (LVs) has not been widely considered. In the current research, we verified that anlotinib, a tyrosine kinase inhibitor with anti-lymphangiogenesis activity, and SAR131675, a selective VEGFR-3 inhibitor, effectively decreased the density of tumor lymphatic vessels in mouse cancer models, further enhancing drug accumulation in tumor tissue. By combining anlotinib with therapeutic drugs, including doxorubicin (Dox), liposomal doxorubicin (Lip-Dox), and anti-PD-L1 antibody, we observed improved anti-tumor efficacy in comparison with monotherapy regimens. Meanwhile, this strategy significantly reduced tumor metastasis and elicited stronger anti-tumor immune responses. Our work describes a new, clinically transferrable approach to augmenting intratumoral drug accumulation, which shows great potential to address the current, unsatisfactory efficacies of therapeutic drugs without introducing metastatic risk.
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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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR THERAPY
·
2024
·
IF 12.1
Xiaozhen Kang,Yifeng Han,Mengdi Wu,Yuxin Li,Peng Qian,Chuning Xu,Zhengyun Zou,Jie Dong,Jiwu Wei
Tumor necrosis factor (TNF) has been recognized as an immune activation factor in tumor immunotherapy. Our study demonstrated that TNF blockade markedly enhanced the antitumor efficacy of oncolytic adenovirus (AdV) therapy. To minimize systemic side effects, we engineered a recombinant oncolytic AdV encoding a TNF inhibitor (AdV-TNFi) to confine TNF blockade within the tumor microenvironment (TME). AdV-TNFi significantly improved therapeutic outcomes across various solid tumor models, including four murine and two golden hamster cancers. Immune cell profiling identified CD8 + T cells as the primary mediators of AdV-TNFi-induced antitumor effects, rather than CD4 + T or NK cells. Additionally, AdV-TNFi significantly decreased the infiltration of suppressive myeloid-derived immune cells within the TME and promoted long-term antitumor immune surveillance. Further investigation indicated that TNFR2, more than TNFR1, is pertinent to the immunosuppressive TME, with a recombinant AdV-encoding anti-TNFR2 demonstrating comparable antitumor efficacy to AdV-TNFi. Moreover, AdV-TNFi enhanced the antitumor efficacy of gemcitabine and immune checkpoint blockades (ICBs), such as anti-PD-L1 and anti-TIGIT antibodies, in pancreatic carcinoma and the anti-EGFR antibody in colon carcinoma. In conclusion, intratumoral blockade of the TNF/TNFR2 axis using AdV augments cancer immunotherapy efficacy while mitigating the risks associated with systemic TNF or TNFR2 suppression, warranting further clinical investigation.
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
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2022
·
IF 18.027
Xue-Feng Bai,Ying Chen,Mei-Zhen Zou,Chu-Xin Li,Yu Zhang,Min-Jie Li,Si-Xue Cheng,Xian-Zheng Zhang
Recent advances in tumor immunotherapy mainly tend to remodel the immunosuppressive tumor microenvironment (TME) for immune enhancement. However, the complexity of TME makes it unlikely to achieve satisfactory therapeutic effects with any single intervention alone. Here, we focus on exposing intrinsic features of tumor cells to trigger direct pleiotropic antitumor immunity. We develop a photosensitive nanointerferer that is engineered with a nanoscale metal–organic framework decorated with tumor cell membranes for targeted delivery of a photosensitizer and small interfering RNA, which is used to knock down cyclin-dependent kinase 4 (Cdk4). Cdk4 blockade can arrest the cell cycle of tumor cells to facilitate antigen exposure and increase the expression level of programmed cell death protein ligand 1 (PD-L1). Under laser irradiation, photodynamic damage triggered by the nanointerferer induces the release of tumor antigens and recruitment of dendritic cells (DCs), thereby promoting the antitumor activity of CD8+ T cells in combination with anti-PD-L1 antibodies. Ultimately, these events markedly retard tumor progression in a mouse model of ectopic colon tumor with negligible adverse effects. This study provides an alternative treatment for effective antitumor immunity by exciting the intrinsic potential of tumor cells to initiate immune responses while reducing immune-related toxicities.
研究领域:
癌症免疫疗法
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纳米技术
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光动力治疗
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分子生物学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2024
·
IF 13
Shiyan Fu,Yong Li,Li Shen,Yonglai Chen,Jingxuan Lu,Yonghong Ran,Yazhen Zhao,Hong Tang,Longfei Tan,Qinyang Lin,Yuhui Hao
Unavoidable damage to normal tissues and tumor microenvironment (TME) resistance make it challenging to eradicate breast carcinoma through radiotherapy. Therefore, it is urgent to develop radiotherapy sensitizers that can effectively reduce radiation doses and reverse the suppressive TME. Here, a novel biomimetic PEGylated Cu 2 WS 4 nanozyme (CWP) with multiple enzymatic activities is synthesized by the sacrificing template method to have physical radiosensitization and biocatalyzer-responsive effects on the TME. Experiment results show that CWP can improve the damage efficiency of radiotherapy on breast cancer cell 4T1 through its large X-ray attenuation coefficient of tungsten and nucleus-penetrating capacity. CWP also exhibit strong Fenton-like reactions that produced abundant ROS and GSH oxidase-like activity decreasing GSH. This destruction of redox balance further promotes the effectiveness of radiotherapy. Transcriptome sequencing reveals that CWP induced ferroptosis by regulating the KEAP1/NRF2/HMOX1/GPX4 molecules. Therefore, owing to its multiple enzymatic activities, high-atomic W elements, nucleus-penetrating, and ferroptosis-inducing capacities, CWP effectively improves the efficiency of radiotherapy for breast carcinoma in vitro and in vivo. Furthermore, CWP-mediated radiosensitization can trigger immunogenic cell death (ICD) to improve the anti-PD-L1 treatments to inhibit the growth of primary and distant tumors effectively. These results indicate that CWP is a multifunctional nano-sensitizers for radiotherapy and immunotherapy.
研究领域:
纳米技术
·
肿瘤学
·
放射生物学
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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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2021
·
IF 4.749
Yingying Zhang,Tiange Wang,Yinping Zhuang,Tiandi He,Xiaoli Wu,Lin Su,Jun Kang,Jin Chang,Hanjie Wang
With the development of technology, adjuvant immunotherapy has become a promising strategy for prevention of postoperative tumor regression and metastasis by stimulating the host immune response. However, the therapeutic effects are still unsatisfactory due to the lack of synergy between different methods. In this study, an efficient synergistic immunotherapy system based on injectable sodium alginate hydrogels was designed to inhibit in situ recurrence and metastasis at the same time. On the one hand, an injectable sodium alginate (SA) hydrogel microsystem loaded with toll-like receptor (TLR) agonists (CpG ODNs) was synthesized for inhibiting in situ recurrence, and then carcinoembryonic antigen (CEA) probe was also added to detect CEA based on fluorescence resonance energy transfer (FRET) technology to monitor the occurrence and development of tumor recurrence. On the other hand, an anti-programmed cell death 1 ligand 1 antibody (anti-PD-L1)-modified SA nanogel loaded with indocyanine green (ICG@SA-anti-PD-L1 nanogel) was prepared for diagnosing and inhibiting lung metastasis by assisting orthotopic tumor therapy. In vitro and in vivo results demonstrated that this SA micro/nanosystem could monitor and inhibit postoperative recurrence and metastasis. We hope that this micro/nano-synergistic system will become an effective strategy for postoperative adjuvant immunotherapy.
研究领域:
肿瘤学
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免疫学
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生物材料
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纳米技术
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2021
·
IF 9.776
Minglu Zhou,Chaohui Luo,Zhou Zhou,Lian Li,Yuan Huang
Triple negative breast cancer (TNBC) with highly metastatic features generally does not respond to anti–programmed cell death 1 ligand 1 (PD-L1) therapy due to multiple immunosuppressive mechanisms to exclude and disable T cells . Here, we develop a polymer-based combinatory approach consisting of both immunogenic cell death (ICD)-inducing and CXCR4-inhibiting function to prime tumor microenvironment and improve anti-PD-L1 therapy in TNBC. Our findings revealed that the combination therapy was able to spur the T cell response in primary tumors by increasing the tumor immunogenicity to recruit T cells, removing the physiological barriers of intratumoral fibrosis and collagen to increase T cell infiltration , and reducing the immunosuppressive cells to revive T cells. Meanwhile, such approach efficiently inhibited the formation of pre-metastatic niche in abscopal lung. Because of the significant promotion of anti-tumor and anti-metastasis immunity, the non-responding TNBC gained robust responsiveness to anti-PD-L1 therapy which resulted in complete eradication of orthotopic tumors, inhibition of pulmonary metastasis , and durable memory effects against tumor recurrence . Our work provided a generalizable approach of simultaneous ICD induction and CXCR4 blockade to apply anti-PD-L1 therapy in TNBC.
研究领域:
肿瘤学
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免疫疗法
·
癌症生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today
·
2024
·
IF 21.1
Yao Yang,Xiaotong Liang,Qimanguli Saiding,Jiachan Lin,Jinyuan Li,Wenyan Wang,Ping Huang,Li Huang,Wenfeng Zeng,Jinhai Huang,Hongzhong Chen,Wei Tao,Xiaowei Zeng
Photodynamic therapy (PDT) can enhance immune checkpoint blockade (ICB) antitumor immunity. However, PDT can significantly exacerbate the hypoxic tumor microenvironment and stimulate tumor neovascularization, promoting tumor invasion and metastasis. Camptothecin can inhibit angiogenesis by down-regulating hypoxia-inducible factor 1α (HIF-1α). Therefore, this study proposed to combine camptothecin with PDT for the first time to alleviate the disadvantage of PDT, and play its dual role of chemotherapy and antiangiogenesis. Here, a light-activated nanocarrier crosslinked the anti-PD-L1, photosensitizer, and camptothecin prodrug mildly with a thioketal bond for checkpoint blockade immunoregulation was designed. Firstly, photosensitizer-induced PDT and immunogenic cell death effect significantly increase T cell infiltration (33.3 % CD8 + increase), enhancing ICB antitumor immunity. Secondly, the antiangiogenic effect of camptothecin was beneficial for alleviating hypoxic tumor microenvironment exacerbated by PDT (HIF-1α expression decreased in tumor cells). Thirdly, light-activated release facilitates tumor accumulation (3.22 times) and controlled drug release. Thus, the immune checkpoint blockade combined with PDT and an antiangiogenic therapy of camptothecin creates a positive feedback co-delivery platform that exemplifies cascaded synergistic tumor therapy by checkpoint blockade immunoregulation. Besides, it also introduces a new strategy for combining small molecule drugs with macromolecules like proteins to treat various diseases.
研究领域:
肿瘤学
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免疫治疗
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纳米技术
·
药学
✓ 已验证
产品关联
DOI
高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Sijia Zhang,Yuanji Feng,Meng Meng,Zhen Li,Huixin Li,Lin Lin,Caina Xu,Jie Chen,Kai Hao,Zhaohui Tang,Huayu Tian,Xuesi Chen
As a representative of tumor immunotherapy, tumor vaccine can inhibit tumor growth by activating tumor-specific immune response, which has the advantages of relatively low toxicity and high efficiency, and has attracted much attention in recent years. However, there are still difficulties in how to effectively deliver tumor vaccines in vivo and make them work efficiently. It is a relatively mature method to load tumor specific antigens with suitable carriers to produce tumor vaccines. Here, a generally minimalist construction method of tumor nanovaccine was developed. A high-efficiency tumor nanovaccine (NV) was prepared in one step by a biomineralization-like method, which contained ovalbumin (OVA, model antigen), unmethylated cytosine-phosphate-guanine (CpG, adjuvant) and Mn-NP (carrier and adjuvant). NV not only showed good tumor preventive effect, but also could successfully inhibited tumor development and metastasis when combined with anti-PD-L1, and induced long-term immune memory effect. However, the method of screening tumor specific antigen to construct nanovaccine is cumbersome and tumors are heterogeneous. Therefore, surgically resected tumor tissue is the best source of antigens for preparing tumor vaccines. Next, based on the strong loading ability of the carrier, we designed a personalized tumor nanovaccine (PNV) using the supernatant of tumor abrasive fluid (STAF) as antigen based on the generally minimalist tumor nanovaccine construction strategy. PNV combined with anti-PD-L1 could successfully inhibit post-surgical tumor recurrence and induce strong and durable immune memory effects. This study presents a novel, general, and minimalist strategy to construct high-efficiency personalized nanovaccine, which has a wide range of potential applications in the field of tumor treatment.
研究领域:
肿瘤学
·
免疫学
·
纳米技术
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Research
·
2023
·Vol. 27
·期 1
·1-22
·
IF 11.3
Shen Shuilin,Zhang Zimeng,Huang Haixiao,Yang Jing,Tao Xinyue,Meng Zhengjie,Ren Hao,Li Xueming
Background Immunogenic cell death (ICD) induced by different cancer treatments has been widely evaluated to recruit immune cells and trigger the specific antitumor immunity. However, cancer associated fibroblasts (CAFs) can hinder the invasion of immune cells and polarize the recruited monocytes to M2-type macrophages, which greatly restrict the efficacy of immunotherapy (IT). Methods In this study, an injectable hydrogel induced by copper (Cu) has been designed to contain antibody of PD-L1 and nitric oxide (NO) donor. The therapeutic efficacy of hydrogel was studied in 4T1 cells and CAFs in vitro and 4T1 tumor-bearing mice in vivo. The immune effects on cytotoxic T lymphocytes, dendritic cells (DCs) and macrophages were analyzed by flow cytometry. Enzyme-linked immunosorbent assay, immunofluorescence and transcriptome analyses were also performed to evaluate the underlying mechanism. Results Due to the absorbance of Cu with the near-infrared laser irradiation, the injectable hydrogel exhibits persistent photothermal effect to kill cancer cells. In addition, the Cu of hydrogel shows the Fenton-like reaction to produce reactive oxygen species as chemodynamic therapy, thereby enhancing cancer treatment and amplifying ICD. More interestingly, we have found that the released NO can significantly increase depletion of CAFs and reduce the proportion of M2-type macrophages in vitro. Furthermore, due to the amplify of ICD, injectable hydrogel can effectively increase the infiltration of immune cells and reverse the immunosuppressive tumor microenvironment (TME) by regulating CAFs to enhance the therapeutic efficacy of anti-PD-L1 in vivo. Conclusions The ion induced self-assembled hydrogel with NO could enhance immunotherapy via amplifying ICD and regulating CAFs. It provides a novel strategy to provoke a robust antitumor immune response for clinical cancer immunotherapy. Graphical Abstract
研究领域:
肿瘤学
·
免疫学
·
生物医学工程
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Coatings
·
2023
·Vol. 13
·期 8
·1400
·
IF 3.4
Yuyan Peng,Li Jiang,Yifan Li,Xiaoping Yu
Soluble programmed death-ligand 1 (sPD-L1) levels vary widely among different stages of tumor development, so the direct quantification of sPD-L1 as a cancer biomarker is useful in cancer diagnosis, prognosis and therapeutic assessment. There is an urgent need for an sPD-L1 detection method with a broad detection range and high sensitivity for monitoring cancer progression and evaluating the effectiveness of immunotherapy in real time. Herein, we have reported an enzyme-free, label-free surface plasmon resonance imaging (SPRi) sensor based on an aptamer/sPD-L1/anti–PD-L1 sandwich structure with gold nanoparticle (AuNP) signal enhancement for the ultrasensitive quantitative measurement of sPD-L1 for the first time. The gold chip of the SPRi sensing platform was modified by DNA aptamers, sPD-L1 was specifically adsorbed on the surface of a DNA aptamer-modified gold chip and then coupled with anti–PD-L1. Thus, the detection of sPD-L1 at different concentrations was realized through the formation of an aptamer/sPD-L1/anti–PD-L1 sandwich structure. We also enhanced the SPR signal via AuNPs to further improve sensor sensitivity. The SPRi sensor is able to measure sPD-L1 within a linear range of 50 pM–10 nM and 100 fM–50 pM, and the minimum detection limit is 19 fM. The sensor is designed to be widely applicable, with better accuracy and reliability for more application scenarios. The prepared SPRi sensor shows great potential in improving the sensitivity of detecting sPD-L1. The proposed method demonstrates the excellent performance of the SPRi sensor and provides a possibility for the establishment of effective clinical assay methods in the future.Keywords:programmed death-ligand 1;surface sandwich assay;DNA aptamer/antibody bioreceptor pair;surface plasmon resonance;tumor biomarker
研究领域:
癌症生物学
·
生物传感器
·
纳米技术
·
免疫学
·
分析化学
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Mengqin Gu,Linglin Zhang,Liying Hao,Kun Wang,Wei Yang,Zhenqi Liu,Zixue Lei,Yinmo Zhang,Wei Li,Li Jiang,Xiyu Li
Designing a novel nanoplatform that integrates multimodal imaging and synergistic therapy for precision tumor nanomedicines is challenging. Herein, we prepared rare-earth ion-doped upconversion hydroxyapatite (FYH) nanoparticles as nanocarriers coated and loaded respectively with polydopamine (PDA) and doxorubicin (DOX), i.e., FYH-PDA-DOX, for tumor theranostics. The developed FYH-PDA-DOX complexes exhibited desirable photothermal conversion, pH/near-infrared-irradiation-responsive DOX release, and multimodal upconversion luminescence/computed tomography/magnetic resonance imaging performance and helped monitor the metabolic distribution process of the complexes and provided feedback to the therapeutic effect. Upon 808 nm laser irradiation, the fast release of DOX facilitated the photothermal–chemotherapy effect, immunogenic cell death, and antitumor immune response. On combining with the anti-programmed cell death 1 ligand 1 antibody, an enhanced tri-mode photothermal-chemo-immunotherapy synergistic treatment against tumors can be realized. Thus, this treatment elicited potent antitumor immunity, producing appreciable T-cell cytotoxicity against tumors, amplifying tumor suppression, and extending the survival of mice. Therefore, the FYH-PDA-DOX complexes are promising as a smart nanoplatform for imaging-guided synergistic cancer treatment.
研究领域:
纳米医学
·
癌症治疗
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医学成像
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免疫疗法
·
药学
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Meng Wei,Xiaobo Wang,Yunhai Mo,Cunqing Kong,Mengqi Zhang,Guanhua Qiu,Zhihong Tang,Jie Chen,Feixiang Wu
Introduction Current therapeutic strategies, including immune checkpoint blockade (ICB), exhibit limited efficacy in treating hepatocellular carcinoma (HCC). Nanoparticles, particularly those that can accumulate specifically within tumors and be activated by sonodynamic therapy (SDT), can induce immunogenic cell death (ICD); however, ICD alone has not achieved satisfactory therapeutic effectiveness. This study investigates whether combining ICB with ICD induced by nanoparticle-mediated SDT could enhance anti-tumor immunity and inhibit HCC growth.Methods We developed an iron-based micelle nanodelivery system encapsulating the Near-Infrared Dye IR-780, which was surface-modified with a cyclic tripeptide composed of arginine-glycine-aspartic acid (cRGD). This led to the synthesis of targeted IR780@FOM-cRGD nanoparticles. These nanoparticles were specifically engineered to kill tumor cells under sonication, activate immunogenic cell death (ICD), and be used in conjunction with immune checkpoint blockade (ICB) for the treatment of hepatocellular carcinoma (HCC).Results The synthesized IR780@FOM-cRGD nanoparticles had an average diameter of 28.23±1.750 nm and a Zeta potential of −23.95±1.926. Confocal microscopy demonstrated that IR780@FOM-cRGD could target HCC cells while minimizing toxicity to healthy cells. Upon sonodynamic activation, these nanoparticles consumed significant amounts of oxygen and generated substantial reactive oxygen species (ROS), effectively killing tumor cells and inhibiting the proliferation, invasion, and migration of H22 cells. Hemolysis assays confirmed the in vivo safety of the nanoparticles, and in vivo fluorescence imaging revealed significant accumulation in tumor tissues. Mouse model experiments showed that combining ICB(which induced by Anti-PD-L1) with ICD (which induced by IR780@FOM-cRGD), could effectively activated anti-tumor immunity and suppressed tumor growth.Discussion This study highlights the potential of IR780@FOM-cRGD nanoparticles to facilitate tumor eradication and immune activation when used in conjunction with Anti-PD-L1 therapy. This combination represents a non-invasive, efficient, and targeted approach for the treatment of hepatocellular carcinoma (HCC). By integrating sonodynamic therapy with immunotherapy, this strategy promises to substantially improve the effectiveness of traditional treatments in combating HCC, offering new avenues for clinical application and therapeutic innovation.
研究领域:
肿瘤学
·
纳米技术
·
免疫治疗
·
癌症生物学
·
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）