BIOMATERIALS
·
2025
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IF 12.9
Zhanxue Xu,Xinrui Yang,Xingyu Lu,Dandan Su,Yidan Wang,Huixing Wu,Zhenhua Zhang,Changrui Long,Liqian Su,Yanyu Wang,Hongbo Chen,Shijian Xiang,Benjie Zhou
Combination therapies for melanoma face challenges due to asynchronous drug delivery and associated toxicity, underscoring the need for advanced delivery systems. While immune checkpoint inhibitors (ICIs) enhance T cell activity, optimal cytotoxic responses require efficient antigen presentation by mature dendritic cells (DCs), which are often functionally impaired in the tumor microenvironment. Thus, effective treatment requires coordinated T cell activation, DC-mediated priming, and direct tumor suppression. Herein, wild Glycyrrhiza uralensis Fisch roots-derived nanovesicles (GC NV) are demonstrated to be effective inhibitors of melanoma proliferation. The vesicles exert this activity through the intracellular delivery of encapsulated miRNA (miR2916) and bioactive molecules (isoliquiritigenin), with this capacity for intracellular delivery extending to the STING agonist DMXAA. We also demonstrate how chemical modification can be used to install PD-L1 antibodies on the membrane surface of these GC NV, imbuing these vesicles with selectivity for tumor cells. Combining DMXAA encapsulation with surface-displayed PD-L1 antibodies creates vesicles (GP@DMX NV) that both promote DCs maturation and elicit CD8 + T cell response. Our multifunctional GP@DMX NV reverse the immunosuppressive microenvironment of melanoma and significantly enhance the immunotherapeutic potential of immune checkpoints.
研究领域:
肿瘤学
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药剂学
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免疫学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR CARCINOGENESIS
·
2024
·
IF 3
Qi Zhang,Chenying Yang,Zhijian Ma,Liangwen Ye,Yunfeng Wu,Caiyun Zhong,Ye Shi,Mingming Zhu
Sulforaphane (SFN) exerts anticancer effect on various cancers including gastric cancer. However, the regulatory effect of SFN on programmed death-ligand 1 (PD-L1) and checkpoint blockade therapy in gastric cancer have not been elucidated. Here we demonstrated that SFN suppressed gastric cancer cell growth both in vitro and in vivo study. SFN upregulated PD-L1 expression through activating ΔNP63α in gastric cancer cells. Further, we found that SFN impaired the anticancer effect of anti-PD-L1 monoclonal antibody (α-PD-L1 mab) on gastric cancer cells. These results uncover a novel PD-L1 regulatory mechanism and the double-edged role of SFN in gastric cancer intervention.
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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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2021
·Vol. 22
·期 24
·13314
·
IF 5.924
Feng Guo,Junfeng Ke,Zhengdong Fu,Wenzhao Han,Liping Wang
Cell penetrating peptides (CPPs) are peptides that can directly adapt to cell membranes and then permeate into cells. CPPs are usually covalently linked to the surface of nanocarriers to endow their permeability to the whole system. However, hybrids with lipids or polymers make the metabolism much more sophisticated and even more difficult to determine. In this study, we present a continuous sequence of 18 amino acids (FFAARTMIWY(d-P)GAWYKRI). It forms nanospheres around 170 nm, which increase slightly after loading with siRNA and DOX. Notably, it can be internalized by cancer cells mainly through electronic interactions and PD-L1-mediated endocytosis. Compared with poly-l-lysine and polyethyleneimine, it has a much higher efficiency (about four times) of gene transduction while lowering toxicity. In the treatment of cancer, it causes apoptosis (21%) and inhibits the expression of SURVIVIN protein in vitro. In vivo, it shows good biocompatibility as there are no changes in mice’s body weight. When administering peptide-siRNA-DOX, tumor growth is inhibited the most (about three times). These results above prove the sequence to be a good candidate for gene therapy and drug delivery.Keywords:peptide;self-assembly;gene therapy;PD-L1
研究领域:
癌症治疗
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纳米技术
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药物递送系统
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Applied Materials Today
·
2022
·
IF 8.663
Ruirui Zhang,Liping Zhong,Xiuli Liu,Xiyu Liu,Qiaoying Chen,Pan Wu,Jian He,Yongmei Li,Yongxiang Zhao,Ziqun Liu,Yan Zu,Yong Huang,Bing Wang
Immunotherapy has made encouraging progress in the field of cancer treatment. Among them, the programmed cell death-ligand 1 (PD-L1) antibody-mediated immunotherapy has stimulated the development of various carrier delivery systems. Inspired by related researchs, in this study, we prepare core-shell structured poly(lactide-co-glycolide) (PLGA) microcapsules as a drug delivery system through microfluidics technology, loaded with PD-L1 aptamers and chemotherapy drug docetaxel. The PD-L1 aptamer loaded in the nuclear layer binds to the PD-L1 molecule produced by tumor cells, blocking the immune checkpoint protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway. As a result, phagocytosis of tumor cells is promoted by using lipopolysaccharide (LPS) induced tumor associated macrophages. Furthermore, docetaxel in the shell is further released, inhibiting tumor cell growth as the PLGA microcapsules degrade. More importantly, the combination of PD-L1 aptamers and the chemotherapy drug docetaxel improved the immune response of the tumor. It showed significant anti-tumor activity and reduced systemic side effects in the melanoma model. At present, more and more nucleic acid aptamers as affinity reagents that can replace antibodies have been used to improve tumor treatment. Therefore, this therapeutic strategy provides more possibilities for tumor treatment by combining aptamer molecules with chemotherapy drugs when exploring more effective combination drugs.
研究领域:
癌症治疗
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药物递送系统
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免疫学
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制药学
✓ 已验证
产品关联
DOI
高影响因子
Nature Biomedical Engineering
·
2019
·Vol. 3
·期 4
·306-317
·
IF 17.135
Yao Han,Lan Jiang,Li Chushu,Shi Hubing,Brosseau Jean-Philippe,Wang Huanbin,Lu Haojie,Fang Caiyun,Zhang Yao,Liang Lunxi,Zhou Xiaolin,Wang Chaojun,Xue Yu,Cui Yun,Xu Jie
Checkpoint blockade therapy targeting the programmed-death ligand 1 (PD-L1) and its receptor programmed cell death 1 promotes T-cell-mediated immunosurveillance against tumours, and has been associated with marked clinical benefit in cancer patients. Antibodies against PD-L1 function by blocking PD-L1 on the cell surface, but intracellular storage of PD-L1 and its active redistribution to the cell membrane can minimize the therapeutic benefits, which highlights the importance of targeting PD-L1 throughout the whole cell. Here, we show that PD-L1 is palmitoylated in its cytoplasmic domain, and that this lipid modification stabilizes PD-L1 by blocking its ubiquitination, consequently suppressing PD-L1 degradation by lysosomes. We identified palmitoyltransferase ZDHHC3 (DHHC3) as the main acyltransferase required for the palmitoylation of PD-L1, and show that the inhibition of PD-L1 palmitoylation via 2-bromopalmitate, or the silencing of DHHC3, activates antitumour immunity in vitro and in mice bearing MC38 tumour cells. We also designed a competitive inhibitor of PD-L1 palmitoylation that decreases PD-L1 expression in tumour cells to enhance T-cell immunity against the tumours. These findings suggest new strategies for overcoming PD-L1-mediated immune evasion in cancer.
研究领域:
癌症免疫学
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分子生物学
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免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
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IF 12.9
Rui Hu,Xin Jiang,Lijie Zhu,Rui Meng,Rongbo Yang,Wenjie Sun,Zhenzhou Zhao,Yuehua Lyu,Ruoyuan Huang,Fei Xue,Mengke Shi,Zaigang Zhou,Jianliang Shen,Congying Xie
Currently, certain lung cancer patients exhibit resistance to radiotherapy due to reduced DNA damage under hypoxic conditions and the cytoprotective and immune-resistance effect caused by increased programmed death ligand-1 (PD-L1) and Cyclooxygenase 2 (COX-2) expression after radiotherapy. At present, existing nanoparticles or drugs could hardly effectively, and easily address these obstacles faced by highly effective radiotherapy simultaneously, especially the simultaneous depression of PD-L1 and COX-2. In this study, it is newly proved that some typical nitric oxide (NO) gas donors could co-inhibit PD-L1 and COX-2 expression, revealing the possible not fully proven role of NO in reversing tumor immunotherapy resistance. Then, to realize selective NO generation in tumors, a simple tumor glutathione (GSH) responsive NO gas nanogenerator named SAB-NO nanoparticles was designed and prepared, which was composed of the NO donor Isoamyl Nitrite conjugated with serum albumin (SAB). By doing this, SAB-NO nanoparticles more effectively sensitized radiotherapy through breaking the cytoprotective effects faced by radiotherapy in vitro by generating more DNA damage through reversing tumor hypoxia and impairing the DNA damage repair process through decreasing PD-L1 expression. Then, the combination therapy of SAB-NO nanoparticles and radiotherapy effectively transformed cold tumors into hot ones through avoiding some potential immune-resistance effects induced by radiotherapy treatment alone through PD-L1 and COX-2 co-inhibition. In conclusion, the combined treatment of radiotherapy and SAB-NO nanoparticles finally almost completely suppressed the growth of lung tumors, revealing the novel role of NO donors in sensitizing tumor immunotherapy by avoiding the potential cytoprotective and immune-resistance effects.
研究领域:
肿瘤学
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免疫学
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药剂学
✓ 已验证
DOI
PubMed
高影响因子
Cell Metabolism
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2025
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IF 30.9
Yizeng Fan,Weichao Dan,Yuzhao Wang,Zhiqiang Ma,Yanlin Jian,Tianjie Liu,Mengxing Li,Zixi Wang,Yi Wei,Bo Liu,Peng Ding,Yuzeshi Lei,Chendong Guo,Jin Zeng,Xiaolong Yan,Wenyi Wei,Lei Li
Itaconate is a metabolite catalyzed by cis- aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.
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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癌症免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2025
·
IF 6.5
Li Gao,Li-Hua Yang,Fang-Cheng Jiang,Wang-Yang Ye,Xin Chen,Zhao-Ji Liu,Rong-Quan He,Wan-Ying Huang,Zhen-Bo Feng,Jin-Liang Kong,Ze-Feng Lai,Gang Chen
Background Although immune checkpoint blocking (ICB) therapeutic agents have significantly improved the survival for many cancer patients, the efficacy of ICB therapy for non-small cell lung cancer (NSCLC) patients remains limited. Combining ICB therapy with other strategies that is able to stimulate tumor immunogenicity or increase infiltration of T cells aroused great concern in cancer therapy.Results Herein, we constructed a kind of AuNP@NH2-PEG-SH/PD-L1 siRNA nanoparticle complex which showed prominent photothermal therapeutic (PTT) effects triggered by NIR laser and could efficiently deliver PD-L1 siRNA into NSCLC cells (knock-down efficiency were 75.8% and 83% in HCC827 and A549 cells). During the process of photothermal stimulation, discrepancies in heat shock protein expression were observed in NSCLC cells. Knocking down PD-L1 expression in NSCLC cells such as A549 and HCC827 cells activated the co-culturing Jurkat cells and enhanced their tumor-killing effect in vitro (cell inhibition rate was 62.65% for HCC827 cells and 57.03% for A549 cells). The gold nanoparticle complexes exhibited remarkable PTT effect for the engrafted NSCLC cells in zebrafish larvas. Furthermore, the nano complexes could promote the activation of the xenografted human peripheral blood mononuclear cells (PBMCs) and enhance the killing of the NSCLC cells in the larvas.Conclusion It is well known that gold nanoparticle is one of the several metal nanoparticles approved for clinical trial by American FDA. This work has demonstrated the outstanding PTT and immunotherapeutic effects of gold nanoparticle complexes on NSCLC, indicating great potential in clinical regiment of lung cancers.
研究领域:
肿瘤学
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免疫学
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生物医学工程
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分子生物学
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转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Jinlian Liu,Ke Song,Bingqi Lin,Zhenfeng Chen,Zirui Zuo,Yixing Fang,Qi He,Xiaodan Yao,Zhifeng Liu,Qiaobing Huang,Xiaohua Guo
Neutrophils and T lymphocytes are closely related to occurrence of immunosuppression in sepsis. Studies have shown that neutrophil apoptosis decreases and T lymphocyte apoptosis increases in sepsis immunosuppression, but the specific mechanism involved remains unclear. In the present study, we found Toll-like Receptor 2 (TLR2) and programmed death-ligand 1 (PD-L1) were significantly activated in bone marrow neutrophils of wild-type mice after LPS treatment and that they were attenuated by treatment with C29, an inhibitor of TLR2. PD-L1 activation inhibits neutrophil apoptosis, whereas programmed death protein 1 (PD-1) activation promotes apoptosis of T lymphocytes, which leads to immunosuppression. Mechanistically, when sepsis occurs, pro-inflammatory factors and High mobility group box-1 protein (HMGB1) passively released from dead cells cause the up-regulation of PD-L1 through TLR2 on neutrophils. The binding of PD-L1 and PD-1 on T lymphocytes leads to increased apoptosis of T lymphocytes and immune dysfunction, eventually resulting in the occurrence of sepsis immunosuppression. In vivo experiments showed that the HMGB1 inhibitor glycyrrhizic acid (GA) and the TLR2 inhibitor C29 could inhibit the HMGB1/TLR2/PD-L1 pathway, and improving sepsis-induced lung injury. In summary, this study shows that HMGB1 regulates PD-L1 and PD-1 signaling pathways through TLR2, which leads to immunosuppression.
研究领域:
免疫学
·
传染病学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Biomaterials Advances
·
2025
·
IF 6
Mingzhu Zhai,Hongxi Tan,Aohong Xu,Benqing Wu,Fang Xie,Yuanzhi Lu,Yi Zheng
Diabetic foot ulcers (DFU), a severe complication of diabetes mellitus, present a global healthcare challenge due to high risks of limb amputation and mortality. This study developed a multifunctional hydrogel dressing, Gelatin Methacryloyl (GelMA) hydrogel loaded with interleukin-4 (IL-4)-engineered exosomes (Exos), designed to synergistically modulate immune responses and enhance angiogenesis for complete diabetic wound repair. The programmed death-ligand 1 (PD-L1)-enriched Exos were engineered via IL-4 overexpression in NIH3T3 fibroblasts. The GelMA hydrogel loaded NIH3T3 fibroblast-derived Exos with IL-4 overexpression (GelMA/Exos IL-4 hydrogel) exhibited favorable physicochemical characteristics, including a three-dimensional porous microstructure, injectability, tissue adhesion, self-healing properties, and sustained moisture retention. In vitro evaluation demonstrated biocompatibility, sustained exosome release, and enhanced viability, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). In a diabetic wound model, the hydrogel significantly accelerated wound closure, promoted re-epithelialization and angiogenesis, and skewed macrophages toward anti-inflammatory M2 polarization while suppressing T-cell proliferation. These findings highlight the dual immunomodulatory and pro-angiogenic efficacy of GelMA/Exos IL-4 hydrogel, offering a promising therapeutic strategy for chronic wound management.
研究领域:
生物材料学
·
再生医学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Oral Science
·
2024
·Vol. 16
·期 1
·1-13
·
IF 10.8
Li Shujin,Feng Tian,Liu Yuantong,Yang Qichao,Song An,Wang Shuo,Xie Jun,Zhang Junjie,Yuan Bifeng,Sun Zhijun
N 1 -methyladenosine (m 1 A) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Using Tgfbr1 and Pten conditional knockout (2cKO) mice, we found the neoplastic transformation of oral mucosa was accompanied by increased m 1 A modification levels. Analysis of m 1 A-associated genes identified TRMT61A as a key m 1 A writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-m 1 A modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, m 1 A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic m 1 A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that m 1 A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Changyong Guo,Shipeng He,Huaxing Shen,Wei Cong,Jinqiu Li,Yajing Ji,Wenjing Huang,Fei Gao,Honggang Hu
Checkpoint blockade immunotherapy has emerged as a transformative approach in cancer treatment by activating tumor-infiltrating T cells. However, the efficacy of PD-L1 blockade is restricted in “cold” tumors, which are characterized by low immunogenicity, presenting a challenge to immunotherapy. This study introduces an innovative strategy, utilizing cathepsin-cleavable N -(2-hydroxypropyl) methacrylamide (HPMA) polymer-assisted combined photodynamic therapy (PDT) and PD-L1 degradation for the first time, effectively treating T cell-deficient tumors. The degradable main-chain polymer, conjugated with photosensitizer porphyrin, facilitates the accumulation of reactive oxygen species (ROS), triggering immunogenic cell death (ICD) and promoting cytotoxic T lymphocytes (CTLs) infiltration into tumors. Multivalent peptide antagonists of PD-L1 promote PD-L1 degradation in lysosomes through receptor crosslinking, overcoming the adaptive cycling of PD-L1 to the tumor cell surface. These findings demonstrate that polymer-assisted PDT and PD-L1 crosslinking degradation represent a potential novel strategy for anti-tumor immunotherapy, providing valuable tools for expanding immunotherapy applications in immunosuppressive cancers.
研究领域:
肿瘤学
·
免疫学
·
药剂学
✓ 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）