JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Zhiyuan Cheng,Yijie Wang,Yao Zhang,Chan Zhang,Mengru Wang,Wei Wang,Jiacheng He,Yang Wang,Hankun Zhang,Qiansen Zhang,Chunyong Ding,Deyan Wu,Linlin Yang,Mingyao Liu,Weiqiang Lu
Nowadays, small-molecule drugs have become an indispensable part of tumor immunotherapy. Accumulating evidence has indicated that specifically blocking PGE2/EP4 signaling to induce robust antitumor immune response represents an attractive immunotherapy strategy. Herein, a 2H-indazole-3-carboxamide containing compound 1 was identified as a EP4 antagonist hit by screening our in-house small-molecule library. Systematic structure–activity relationship exploration leads to the discovery of compound 14, which displayed single-nanomolar EP4 antagonistic activity in a panel of cell functional assays, high subtype selectivity, and favorable drug-like profiles. Moreover, compound 14 profoundly inhibited the up-regulation of multiple immunosuppression-related genes in macrophages. Oral administration of compound 14, either as monotherapy or in combination with an anti-PD-1 antibody, significantly impaired tumor growth via enhancing cytotoxic CD8+ T cell-mediated antitumor immunity in a syngeneic colon cancer model. Thus, these results demonstrate the potential of compound 14 as a candidate for developing novel EP4 antagonists for tumor immunotherapy.
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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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Lipeng Zhu,Dongliang Leng,Ziang Guo,Yuetao Zhao,Kam-Tong Leung,Yeneng Dai,Junnan Li,Qi Zhao
Ferroptosis, triggered by membrane lipid peroxidation (LPO) and diminished antioxidants, can be induced by intracellular iron (II, Fe 2+ ). However, the role of nitric oxide (NO) in causing Fe 2+ overload for ferroptosis remains uncertain. This study reveals that NO can stimulate endogenous Fe 2+ release by upregulating heme oxygenase 1 (HMOX1) expression. Here, ferritin heavy chain (FHC) siRNA and hyaluronic acid (HA)-modified Arg-stabilized zinc peroxide (AZOSH), a non-ferrous-based nanoagent, is synthesized to trigger ferroptosis by inducing intracellular Fe 2+ overload. AZOSH, a self-catalyzed NO nanocomplex, effectively generates NO through a reaction of self-supplied Arginine (Arg) and hydrogen peroxide (H 2 O 2 ), which promotes glutathione (GSH) consumption to downregulate glutathione peroxidase 4 (GPX4) expression and produces peroxynitrite (ONOO − ) to enhance LPO. Meanwhile, NO promotes endo/lysosomal escape of siRNA by damaging membrane structures. Moreover, AZOSH significantly triggers Fe 2+ overload through the synergistic effects of NO-activated HMOX1 expression and FHC siRNA-mediated ferritin sequestration. Additionally, the released Zn 2+ from AZOSH induces oxidative stress by inhibiting mitochondrial function, further promoting ferroptosis. Consequently, AZOSH-mediated ferroptosis exhibits a strong cellular immunogenic response for T-cell activation and infiltration. Importantly, the integration of AZOSH with an anti-PD-1 antibody results in notable antitumor efficacy in vivo . Therefore, this study provides a novel concept of NO-induced ferroptosis, highlighting its role in enhancing PD-1-based immunotherapeutic efficacy.
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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治疗学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-20
·
IF 12.6
Gu Lina,Sun Ying,Bai Tingjie,Shao Sijie,Tang Shumin,Xue Panpan,Cai Wanlin,Qin Xian,Zeng Xuemei,Yan Shuangqian
Elevated copper levels induce tumor cuproptosis and ferroptosis, leading to immunogenic cell death and subsequent antitumor immune responses. However, dysregulated copper metabolism in tumor cells maintains homeostatic copper balance, while hypoxic microenvironments hinder therapeutic efficacy. In this study, we present a nanozyme system, termed Cu ss OMEp, comprising a copper-based nanovector (Cu ss NV) that is PEGylated and loaded with omeprazole, a copper transporter inhibitor, to enhance tumor synergistic immunotherapy by promoting cuproptosis and ferroptosis. Cu ss NV is assembled from dithiodiglycolic acid and copper ions, exhibiting peroxidase, glutathione oxidase, and catalase-like activities, along with responsive degradability. This nanozyme alleviates tumor hypoxia by producing oxygen, induces ferroptosis through the generation of lethal hydroxyl radicals, and depletes glutathione. Additionally, omeprazole increases cellular copper concentration and oxidative stress by inhibiting the intracellular copper-transporting ATPase 1 (ATP7A), enhancing lipoylated protein oligomerization and cuproptosis. In a breast tumor mouse model, Cu ss OMEp elicits robust antitumor immune responses, including dendritic cell maturation and T cell proliferation. When combined with PD-1 antibodies (αPD-1), Cu ss OMEp significantly inhibits tumor metastasis in bilateral and lung metastatic models. This work presents a functional nanozyme system as a promising strategy for synergistic tumor immunotherapy leveraging ferroptosis and cuproptosis Graphical abstract
研究领域:
生物医学工程
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肿瘤学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Jiaxuan Li,Kuirong Mao,Xiandi Meng,Jialiang Wang,Mengfei Zhao,Yue Lv,Yanbao Xin,Huating Sun,Yuning Zhang,Yong-Guang Yang,Tianmeng Sun
Tumor-associated macrophages (TAMs) significantly influence the clinical outcomes of immune checkpoint blockade (ICB) therapy. Strategies aimed at reprogramming TAMs from the immunosuppressive M2 phenotype to the pro-inflammatory M1 phenotype hold promise for enhancing ICB efficacy. Lipopolysaccharide (LPS), a potent Toll-like receptor 4 (TLR4) ligand, can reprogram TAMs toward an M1 phenotype. However, the systemic application of LPS is restricted due to its pronounced pro-inflammatory properties, which limit safe dosing in cancer treatment. To address this, thermosensitive hydrogels offer a viable solution by optimizing drug bioavailability and reducing systemic dissemination. In our study, carboxymethyl chitosan (CS) was incorporated into Pluronic F127 to extend the hydrogel's degradation period, facilitating the localized delivery and accumulation of LPS within tumor sites. Peritumoral injection of this hydrogel enhanced the tumor-inhibitory effects of anti-PD-1 antibodies, significantly improving the survival of 4T1 tumor-bearing mice. The GelF127CS-LPS hydrogel also increased the expression of the activation marker on tumor-infiltrating dendritic cells, promoted a higher M1/M2 TAM ratio, and enhanced CD8 + T cell infiltration into tumors—key indicators of T-cell-mediated anti-tumor immunity. Notably, no significant liver or hematological toxicity was observed with GelF127CS-LPS treatment, underscoring its favorable safety profile. These findings demonstrate the potential of GelF127CS-LPS as a TAMs-modulating agent and a promising combinatorial strategy to boost ICB therapy effectiveness. Statement of significance LPS, a potent TLR4 ligand, can reprogram tumor-associated macrophages (TAMs) toward an M1 phenotype, thereby contributing to tumor inhibition. However, its anti-tumor application is constrained by the contradiction between high-dose toxicity and insufficient efficacy at low doses. To address this issue, we developed a thermosensitive hydrogel encapsulating LPS, GelF127CS-LPS, which allows localized LPS release within the tumor area. This hydrogel reprograms TAMs at a picogram level of LPS to achieve a favorable M1/M2 ratio and promotes the activation of T cell-mediated antitumor immunity without observable toxicity. Consequently, when combined with immune checkpoint blockade (ICB), the hydrogel can inhibit tumor growth and improve overall survival. This study provides an effective method for tumor-targeted therapeutic LPS delivery to enhance the efficacy of ICB.
研究领域:
肿瘤学
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免疫疗法
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药学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Jiaxin Yin,Shengcai Yang,Zengguang Liu,Songchen Zhao,Siyu Sun,Ziling Liu,Quanshun Li
The metabolic reprogramming of immunosuppressive tumor microenvironment (ITME) greatly influences the anti-tumor immunity. Bioinformatic analysis demonstrates that indoleamine 2,3-dioxygenase 1 and 3-hydroxy-3-methylglutaryl coenzyme A reductase (key enzymes of kynurenine (Kyn) and cholesterol metabolism, respectively), are overexpressed in human colon adenocarcinoma tissues. Herein, biomimetic and pH/ROS dual-responsive nanoparticles (PTSK@CRM) loaded with simvastatin and kynureninase (KYNase) are prepared to regulate Kyn and cholesterol metabolism, thereby enhancing the immunotherapeutic efficacy of PD-1 antibody (αPD-1). The monodisperse spherical PTSK@CRM is stable at pH 7.4, while it can release simvastatin and KYNase under low pH and high H 2 O 2 concentration. PTSK@CRM achieves excellently homologous tumor targeting to CT26 cells and induces cell apoptosis more effectively than PTSK. Moreover, PTSK@CRM significantly reduces the contents of Kyn and cholesterol and decreases the activation of the Kyn-AhR pathway in tumor metabolism. In vivo experiments show that PTSK@CRM possesses a favorable tumor-targeting ability to effectively suppress tumor growth and increase the infiltration of immune cells, including CD8 + T cells, CD4 + T cells, M1-like macrophages, and mature dendritic cells. Further, PTSK@CRM reduces the infiltration of immunosuppressive cells, thereby reversing ITME to improve the therapeutic efficacy of αPD-1. Overall, this immune-metabolic therapeutic strategy provides a potential route for remodeling ITME to enhance tumor immunotherapy.
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DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2021
·Vol. 31
·期 28
·2100437
·
IF 18.808
Tong Gao,Zipeng Zhang,Shuang Liang,Shunli Fu,Weiwei Mu,Li Guan,Yang Liu,Qihui Chu,Yuxiao Fang,Yongjun Liu,Na Zhang
Immune checkpoint therapy promotes cytotoxic T lymphocytes (CTLs) activity to eliminate tumors. Nevertheless, their effectiveness in solid tumors is limited by inadequate infiltration of CTLs and suppressive tumor microenvironment (TME). Herein, an anti-PD-1 antibody coupled chemo-photothermal integrated nanoplatform (A/Au@MSMs-P) is proposed to reshape antitumor immunity against cancer. The matrix metalloproteinase-2 (MMP-2) responsive A/Au@MSMs-P promotes the separation of abemaciclib-loaded gold-silica nanoparticles (A/Au@MSMs) and anti-PD-1 antibody, achieving a triple-coordinated strategy to enhance checkpoint blockade therapy. First, chemo-photothermal therapy of A/Au@MSMs induces cell cycle arrest in G1 phase and promotes tumor cells apoptosis to achieve local ablation. Second, immunogenic death of tumor cells promotes the maturation of dendritic cells and recruits antigen-specific CTLs into tumor tissue to promote immune activation. Third, abemaciclib markedly suppresses the proliferation of regulatory T cells (Tregs) to alleviate the immunosuppression of the TME and potentiates the effectiveness of CTLs. This triple-coordinated strategy not only reshapes the antitumor immunity to enhance checkpoint blockade, but also cooperates with chemo-photothermal therapy, leading to improved antitumor efficiency and prolonged survival rate. Taken together, this study presents a promising strategy for improving checkpoint therapy response and has great potential in future cancer therapy.
研究领域:
肿瘤学
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免疫疗法
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纳米医学
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癌症生物学
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产品关联
DOI
高影响因子
ACS Nano
·
2019
·
IF 13.903
Weidong Nie,Wei Wei,Liping Zuo,Chengliang Lv,Fan Zhang,Gui-Hong Lu,Feng Li,Guanghao Wu,Li−Li Huang,Xiaobo Xi,Hai-Yan Xie
Although adoptive T-cell therapy has been successful in hematological malignancy treatment, its application in solid tumors remains a great challenge. Here, using a pH-sensitive benzoic–imine bond and inverse electron-demand Diels–Alder cycloaddition, we prepared magnetic nanoclusters (NCs) armed with responsive PD-1 antibody (aP), which could then bind onto effector T cells due to their PD-1 expression. After adoptive transfer, the magnetization and superparamagnetism of NCs enabled us to magnetically recruit effector T cells and aP simultaneously to tumor sites with MRI guidance. Owing to the acidic intratumoral microenvironment, the benzoic–imine bond then hydrolyzed, leading to the release of aP. The therapeutic effects of adoptive T cells and free aP could thus be spatiotemporally coupled. As a result, we achieved inhibition of tumor growth with few side effects, demonstrating the great promise of such a chemical approach for safe and high-performance adoptive T-cell therapy against solid tumors.
研究领域:
癌症免疫治疗
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纳米技术
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生物医学工程
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2021
·
IF 9.776
Mengshi Jiang,Bing Qin,Lihua Luo,Xiang Li,Yingying Shi,Junlei Zhang,Zhenyu Luo,Chunqi Zhu,Guannan Guan,Yongzhong Du,Jian You
The hypoxic tumor microenvironment (TME) hinders the effectiveness of immunotherapy . Alleviating tumor hypoxia to improve the efficacy of immune checkpoint inhibitors (ICIs) represented by programmed cell death protein 1 (PD-1) antibody has become a meaningful strategy. In this study, we adopted three methods to alleviate hypoxia, including direct oxygen delivery using two different carriers and an indirect way involving HIF-1α inhibition. Both in vivo and in vitro experiments showed that liposomes modified with perfluorocarbon or hemoglobin ( [email protected] or [email protected] ) were able to efficiently load and release oxygen, relieving tumor hypoxia. However, the gas release behavior of [email protected] was uncontrollable, which might induce acute hyperoxia side effects during intravenous injection and reduce its biosafety. In contrast, whether administered locally or systemically, [email protected] revealed high animal tolerance, and was much safer than commercial HIF-1α inhibitor (PX-478), displaying prospects as a promising oxygen carrier for clinical practice. Pharmacodynamic experiments suggested that [email protected] helped PD-1 antibody break the therapeutic bottleneck and significantly inhibited the progression of 4 T1 breast cancer. But in CT26 colon cancer , the combination therapy failed to suppress tumor growth. After in-depth analysis and comparison, we found that the ratio of M1/M2 tumor associated macrophages (TAMs) between these two tumor models were dramatically different. And the lower M1/M2 ratio in CT26 tumors limited the anti-tumor effect of combination therapy. In this study, three methods for alleviating tumor hypoxia were compared from the perspectives of biosafety, efficacy and clinical applicability. Among them, [email protected] stood out, and its combined use with PD-1 antibody exhibit a distinct synergistic suppression effect on tumors with more M1 macrophages presented in the microenvironment. Our work provided a good reference for improving the efficacy of PD-1 antibody by alleviating tumor hypoxia.
研究领域:
肿瘤学
·
免疫疗法
·
药理学
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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
Small
·
2023
·
IF 13.3
Qiuqun Xiao,Jinyan Huang,Xing Wang,Zehong Chen,Weiqi Zhang,Fengjiao Liu,Jiejing Li,Zhimou Yang,Jie Zhan,Yanbin Cai
Tumor immunotherapy has become a research hotspot in cancer treatment, with macrophages playing a crucial role in tumor development. However, the tumor microenvironment restricts macrophage functionality, limiting their therapeutic potential. Therefore, modulating macrophage function and polarization is essential for enhancing tumor immunotherapy outcomes. Here, a supramolecular peptide amphiphile drug-delivery system (SPADS) is utilized to reprogram macrophages and reshape the tumor immune microenvironment (TIM) for immune-based therapies. The approach involved designing highly specific SPADS that selectively targets surface receptors of M2-type macrophages (M2-Mφ). These targeted peptides induced M2-Mφ repolarization into M1-type macrophages by dual inhibition of endoplasmic reticulum and oxidative stresses, resulting in improved macrophagic antitumor activity and immunoregulatory function. Additionally, TIM reshaping disrupted the immune evasion mechanisms employed by tumor cells, leading to increased infiltration, and activation of immune cells. Furthermore, the synergistic effect of macrophage reshaping and anti-PD-1 antibody (aPD-1) therapy significantly improved the immune system's ability to recognize and eliminate tumor cells, thereby enhancing tumor immunotherapy efficacy. SPADS utilization also induced lung metastasis suppression. Overall, this study demonstrates the potential of SPADS to drive macrophage reprogramming and reshape TIM, providing new insights, and directions for developing more effective immunotherapeutic approaches in cancer treatment.
研究领域:
癌症免疫治疗
·
纳米技术
·
药学
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免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Shu Liang,Lingyun Xiao,Tian Chen,Paola Roa,Emiliano Cocco,Zhangwen Peng,Liu Yu,Meiying Wu,Jie Liu,Xizhe Zhao,Wenbin Deng,Xiongjun Wang,Chao Zhao,Yang Deng,Yang Mai
Intraperitoneal co-delivery of chemotherapeutic drugs (CDs) and immune checkpoint inhibitors (ICIs) brings hope to improve treatment outcomes in patients with peritoneal metastasis from ovarian cancer (OC). However, current intraperitoneal drug delivery systems face issues such as rapid drug clearance from lymphatic drainage, heterogeneous drug distribution, and uncontrolled release of therapeutic agents into the peritoneal cavity. Herein, we developed an injectable nanohydrogel by combining carboxymethyl chitosan (CMCS) with bioadhesive nanoparticles (BNPs) based on polylactic acid-hyperbranched polyglycerol. This system enables the codelivery of CD and ICI into the intraperitoneal space to extend drug retention. The nanohydrogel is formed by cross-linking of aldehyde groups on BNPs with amine groups on CMCS via reversible Schiff base bonds, with CD and ICI loaded separately into BNPs and CMCS network. BNP/CMCS nanohydrogel maintained the activity of the biomolecules and released drugs in a sustained manner over a 7 day period. The adhesive property, through the formation of Schiff bases with peritoneal tissues, confers BNPs with an extended residence time in the peritoneal cavity after being released from the nanohydrogel. In a mouse model, BNP/CMCS nanohydrogel loaded with paclitaxel (PTX) and anti-PD-1 antibodies (αPD-1) significantly suppressed peritoneal metastasis of OC compared to all other tested groups. In addition, no systemic toxicity of nanohydrogel-loaded PTX and αPD-1 was observed during the treatment, which supports potential translational applications of this delivery system.
研究领域:
药学
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生物医学工程
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肿瘤学
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-15
·
IF 12.6
Liu Yu,Zhang Jia,Lai Chunyu,Wang Wenjun,Huang Yangyue,Bao Xuanwen,Yan Haimeng,Sun Xuqi,Liu Qiqi,Chen Dong,Dai Xiaomeng,Qian Xinyu,Zhao Peng
Immunotherapy, exemplified by immune checkpoint blockade (ICB), has been extensively employed in antitumor treatments. Nevertheless, its efficacy in addressing low-immunogenic tumors has not yielded satisfactory results, primarily due to the depletion and inadequate infiltration of effector T cells within the tumor microenvironment (TME). Here, we construct an injectable water-in-oil emulsion hydrogel to load clinically used Celastrol (Gel@Cel), which addresses the limitations of Cel’s hydrophobicity. Cel can both inhibit tumor cell proliferation and promote tumor cell apoptosis, while simultaneously inducing immunogenic cell death, through activation of the AKT and MAPK pathways. In a model of clinically refractory hepatocellular carcinoma with malignant ascites, intraperitoneal administration of Gel@Cel significantly inhibits tumor progression and activates antitumor immune effects through lipase-controlled release of Cel, as compared to free Cel. Intriguingly, the Gel@Cel induces the activation of dendritic cells, resulting in the infiltration of cytotoxic T cells in the TME of ascites. Furthermore, the administration of Cel increases the expression of programmed cell death protein ligand-1 (PD-L1) in tumor cells. Moreover, combining the PD-1 antibody (αPD-1) with Gel@Cel further enhances the antitumor effect and amplifies the immune activation. In conclusion, Gel@Cel exhibits promising therapeutic potential in the treatment of low-immunogenic tumors, especially when combined with ICB therapy.
研究领域:
肿瘤学
·
药理学
·
免疫学
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Yuzhao Zheng,Fanxue Bu,Chenfeng Xu,Tongyu Wu,Jianping Zhou,Weiyang Shen,Tingjie Yin
Immunosuppressive microenvironment and poor immunogenicity are two stumbling blocks in anti-tumor immune activation. Tumor associated macrophages (TAMs) play crucial roles in immunosuppressive microenvironment, while immunogenic cell death (ICD) is a typical strategy to boost immunogenicity. Herein, we developed a coordinative modular assembly-based self-reinforced nanoparticle, (CaO 2 /TA)-(Fe 3+ /BSA) which integrated CaO 2 , Fe 3+ -tannic acid coordinated networks and albumin under the instruction of molecular dynamics simulation. (CaO 2 /TA)-(Fe 3+ /BSA) could significantly enhance Fenton reaction through Fe 3+ self-reduction and H 2 O 2 self-sufficiency, and simultaneously increased intracellular accumulation of Ca 2+ . The self-augmented Fenton reaction with sufficient reactive oxygen species effectively repolarized TAMs and elicited ICD with Ca 2+ overload. Besides, (CaO 2 /TA)-(Fe 3+ /BSA) was confirmed to self-reinforce deep tumor drug delivery by “treatment-delivery” positive feedback based on gp60-mediated transcytosis and M2-like macrophages repolarization-mediated perfusion promotion. Resultantly, (CaO 2 /TA)-(Fe 3+ /BSA) effectively alleviated immunosuppression, provoked local and systemic immune response and potentiated anti-PD-1 antibody therapy. Our strategy highlights a facile and controllable approach to construct penetrated effective antitumor nano-immunotherapeutic agent.
研究领域:
癌症免疫治疗
·
纳米技术
·
药学
·
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）