International Journal of Biological Sciences
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2025
·Vol. 21
·期 8
·3555
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IF 10
Pengyi Liu,Minmin Shi,Yang Liu,Yihao Liu,Jiayu Lin,Shuyu Zhai,Yizhi Cao,Dongjie Chen,Yongsheng Jiang,Chenghong Peng,Lei Zhang,Chunyong Ding,Lingxi Jiang,Baiyong Shen
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited treatment options and poor response to immunotherapy. The immunosuppressive tumor microenvironment, characterized by a dense extracellular matrix, and immunosuppressive cells, plays a crucial role in this resistance. The cGAS-STING pathway, traditionally recognized for antiviral defense, has emerged as a potential target for cancer immunotherapy due to its ability to activate both innate and adaptive immune responses. Methods: A novel small-molecule STING agonist, D166, was synthesized by incorporating deuterium into the structure, leading to improved stability and activation of the STING pathway. The effects of D166 were evaluated using human pancreatic tumor organoids, mouse pancreatic tumor models, and various in vitro and in vivo assays, including flow cytometry, RNA sequencing, ELISA and western blotting. And an organoid-immune cells co-culture system was established for further investigate the effects on immune cells. Results: D166 demonstrated significant anti-tumor activity, effectively activating the cGAS-STING pathway in a time- and dose-dependent manner. D166 inhibited the progression of pancreatic tumor organoids and mouse pancreatic tumors, reshaping the tumor immune microenvironment. The drug enhanced T cell activation, promoted macrophage polarization toward the M1 phenotype, and increased the infiltration of immune cells. Additionally, D166 acted as a sensitizer for anti-PD-1 therapy, significantly improving therapeutic efficacy in combination treatments. Conclusion: D166 is a novel and stable STING agonist that inhibits pancreatic tumor progression by activating the cGAS-STING pathway and remodeling the tumor immune microenvironment. Its combination with anti-PD-1 antibodies offers a promising strategy for overcoming the immunosuppressive barriers in pancreatic cancer, providing new therapeutic insights and directions.
研究领域:
肿瘤学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Jian Wu,Zhiqiang Chen,Haojie Shang,Yonghua Tong,Wen Deng,Yu He,Xiaozhuo Ba,Zichen Zhong,Yongke Bai,Tao Ye,Xiaoqi Yang,Kehua Jiang,Yijing Liu,Kun Tang
Limited lymphocyte infiltration and insufficient tumor immunogenicity remain major challenges for effective immunotherapy in bladder cancer, particularly in immunologically “cold” tumors with a highly suppressive immune microenvironment. Effective activation of the innate immune system is critical for initiating a robust adaptive anti-tumor immune response, primarily mediated by dendritic cells (DCs). Here, we designed genetically engineered hybrid membrane-coated nanoparticles (HM-MPS NPs) with excellent photothermal stability, tumor-targeting capability, and biocompatibility. HM-MPS NPs demonstrated significant tumor-suppressive effects in multiple preclinical models, including murine subcutaneous, orthotopic, and distant bladder tumor models. By combining photothermal therapy (PTT), a STING agonist (SR717), and antigen presentation, HM-MPS NPs achieve triple activation of DCs, leading to enhanced T-cell activation and a remodeled immune microenvironment. Furthermore, HM-MPS NPs synergize effectively with anti-PD-1 therapy, amplifying immunogenic cell death (ICD) and overcoming immune suppression within the tumor microenvironment. This strategy significantly boosts tumor immunogenicity and enhances anti-tumor immune responses, offering a promising approach for bladder cancer treatment.
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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产品关联
DOI
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2022
·
IF 9.273
Xudong Fan,Tianxiang Yue,Aidi Liu,Xiaowei Xie,Weixiang Fang,Yinghui Wei,Hangsheng Zheng,Hongyue Zheng,Meiqi Zhou,Jigang Piao,Fanzhu Li
Photothermal therapy (PTT) has brought hope for cancer treatments, with hyperthermia-induced immunogenic cell death (ICD), which is a critical part of therapeutically induced antitumor immune responses. Limited immune stimulation response in PTT is the primary reason for incomplete tumor ablation, therefore demonstrating urgent requirements for ICD amplifier. Herein, a sub-10 nm supramolecular nanoassembly was formed by co-assembly of clinically approved aluminum adjuvant and commonly used indocyanine green (ICG) under the assistance of lignosulfonate (LS, a green and sustainable multifunctional lignin derivative) for localized photothermal-immunotherapy of breast cancer. The overall results revealed that LS-Al-ICG is capable of inducing amplified ICD, efficiently eliciting solid immune responses through dendritic cells (DCs) activation and cytotoxic T-cell responses initiation for tumor killing. Moreover, anti-PD-1 therapy blocked the PD-1 pathway and led to remarkable anti-tumor efficacy against laser-irradiated primary tumors and distant tumors by potentiating systemic tumor specific T cell immunity. The results of this study demonstrate a handy and extensible approach for engineering green natural lignin nanoparticles for cancer immunotherapy, which shows promise for delivering other therapeutics in biomedical applications.
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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生物医学工程
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药学
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产品关联
DOI
PubMed
高影响因子
Cell Reports Medicine
·
2025
·
IF 10.6
Liming Gui,Kaiwen Chen,Jingjing Yan,Ping Chen,Wei-Qiang Gao,Bin Ma
The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK family SNF1-like kinase 1 (NUAK1) is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by spliced form of X-box binding protein 1 (XBP1s) downstream of ICD-induced endoplasmic reticulum (ER) stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampens ROS and ICD, and therefore also dampens tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.
研究领域:
癌症研究
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免疫学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Science Advances
·
2020
·Vol. 6
·期 35
·
IF 13.117
Jingjing Liang,Huifang Wang,Wenxiu Ding,Jianxiang Huang,Xuefei Zhou,Huiyang Wang,Xue Dong,Guangyao Li,Enguo Chen,Fei Zhou,Hongjie Fan,Jingya Xia,Bo Shen,Da Cai,Pengxun Lan,Hanliang Jiang,Jun Ling,Zhen Cheng,Xiangrui Liu,Jihong Sun
Mounting evidence suggests that immunotherapies are a promising new class of anticancer therapies. However, the immunosuppressive tumor microenvironment (TME), poor immunogenicity, and off-target toxicity hinder the broader implementation of immunotherapies. Here, we describe a novel strategy combining chemotherapy and immunotherapy to modulate the TME by systemically and concurrently delivering the chemotherapeutic agent SN38 (7-ethyl-10-hydroxycamptothecin) and the STING agonist DMXAA (5,6-dimethylxanthenone-4-acetic acid) into tumors using triblock copolymer nanoparticles, named PS3D1@DMXAA, which enhances antigen cross-presentation and induces the conversion of the immunosuppressive TME to immunogenic TME through the newly found synergistic function between SN38 and STING activation. PS3D1@DMXAA thus shows potent therapeutic efficacy in three mice tumor models and elicits remarkable therapeutic benefit when combined with anti–PD-1 therapy. Our engineered nanosystem offers a rational design of an effective immunotherapy combination regimen to convert uninflamed “cold” tumors into “hot” tumors, addressing the major challenges immunotherapies faced.
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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癌症研究
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-19
·
IF 14.7
Zhang Weiqi,Zeng Yinghua,Xiao Qiuqun,Wu Yuanyuan,Liu Jiale,Wang Haocheng,Luo Yuting,Zhan Jie,Liao Ning,Cai Yanbin
Targeted immunomodulation for reactivating innate cells, especially macrophages, holds great promise to complement current adaptive immunotherapy. Nevertheless, there is still a lack of high-performance therapeutics for blocking macrophage phagocytosis checkpoint inhibitors in solid tumors. Herein, a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor (PAC-SABI) is described, which undergoes biomimetic surface propagation on cancer cell membranes through ligand-receptor binding and enzyme-triggered reactions. By simultaneously blocking CD47 and CD24 signaling, PAC-SABI enhances the phagocytic ability of macrophages in vitro and in vivo, promoting anti-tumor responses in breast and pancreatic cancer mouse models. Moreover, building on the foundation of PAC-SABI-induced macrophage repolarization and increased CD8 + T cell tumor infiltration, sequential anti-PD-1 therapy further suppresses 4T1 tumor progression, prolonging survival rate. The in vivo construction of PAC-SABI-based nano-architectonics provides an efficient platform for bridging innate and adaptive immunity to maximize therapeutic potency.
研究领域:
免疫学
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肿瘤学
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生物技术
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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