Experimental Hematology & Oncology
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2025
·Vol. 14
·期 1
·1-17
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IF 13.5
Ren Xueting,Wu Jinpeng,Li Jing,Zhai Zhen,Li Xiang,Guan Feng,Wang Meng,Ma Xiaobin,Tan Zengqi,Kang Huafeng,Lin Shuai
Background The abundance of PD-L1 on the surface of tumor cells is a critical factor in sensitizing these cells to T cell-mediated immune killing. While abnormal glycosylation of PD-L1 is known to influence its expression and function, the precise regulatory mechanisms remain unclear.Methods This study utilized bioinformatics analysis to explore the role of MGAT3, a key gene involved in the formation of the bisecting GlcNAc structure, in breast cancer (BC). Experimental approaches were employed to increase bisecting GlcNAc levels in BC cells, followed by assessments of PD-L1 expression, CD8+ T cell-mediated cytotoxicity, extracellular vesicle (EV)-associated PD-L1, and PD-L1/PD-1 interaction. Additionally, forskolin, a bisecting GlcNAc agonist, was combined with anti-PD-L1 antibody to evaluate its antitumor effects in vivo.Results MGAT3 was found to be expressed at low levels in BC tissues but positively correlated with CD8+ T cell infiltration. Elevating bisecting GlcNAc levels in BC cells significantly enhanced the cytotoxic efficacy of CD8+ T cells. High bisecting GlcNAc modification promoted PD-L1 degradation via the lysosomal pathway, reducing PD-L1 expression and its binding to PD-1. Furthermore, increased bisecting GlcNAc levels reduced PD-L1 in tumor cell-derived EVs, impairing the EVs’ ability to block CD8+ T cells and indirectly enhancing T cell cytotoxicity. The combined use of forskolin and anti-PD-L1 antibody significantly increased CD8+ T cell abundance and activity, achieving a more effective antitumor response in vivo.Conclusion sThese findings demonstrate that enhancing bisecting GlcNAc modification in BC cells promotes PD-L1 degradation and inhibits its binding to PD-1, thereby boosting CD8+ T cell-mediated cytotoxicity, providing a promising strategy for immune modulation in BC therapy.
研究领域:
癌症生物学
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免疫学
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生物化学
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糖生物学
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分子生物学
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DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Yeyang Sun,Xietao Ye,Lin Yang,Shuo Dong,Chen Chen,Yani Wang,Jianan Qiao,Congyan Liu,Yuping Liu,Yan Chen
Programmed cell death protein 1 (PD-1) inhibitors are integral to contemporary cancer immunotherapy. However, their objective response rate in microsatellite-stable colorectal cancer (MSS CRC) remains below 5 %. This limited efficacy is primarily due to insufficient tumor-infiltrating lymphocytes (TILs), a consequence of the combined effects of low tumor immunogenicity and impaired dendritic cell (DC)-mediated antigen presentation. The combination of ursolic acid (Ua) and ginsenoside Rg3 (Rg3) enhances TIL infiltration by inducing immunogenic cell death (ICD) in tumor cells and promoting DC maturation. Due to their poor oral bioavailability, an oral ZIF nanoplatform was engineered with a chitosan oligosaccharide (Cos) and inulin (In) bilayer coating [(In/Cos)@Ua-Rg3-ZIF] for targeted delivery of Ua and Rg3 to the CRC microenvironment. Efficient dual-drug co-loading was achieved with a loading efficiency of 24.07 wt%. After oral administration, the (In/Cos) coating protects the formulation from degradation in the upper gastrointestinal tract, while specific enzymatic cleavage by colonic microbiota releases Ua-Rg3-ZIF into tumor tissues. The ZIF platform responds to elevated adenosine triphosphate (ATP) in the tumor microenvironment, enabling controlled release of Ua and Rg3 to enhance cytotoxic T lymphocyte (CTL) levels. In vivo studies demonstrate that combining (In/Cos)@Ua-Rg3-ZIF with α-PD-1 results in an 80.86 % tumor inhibition rate, significantly outperforming monotherapies. This strategy presents an innovative oral delivery system capable of resisting gastrointestinal degradation and facilitating microbiota-responsive drug release, effectively enhancing antitumor immunity and improving the therapeutic outcome of immunotherapy in MSS CRC.
研究领域:
纳米医学
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癌症免疫治疗
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药物递送系统
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胃肠道肿瘤学
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微生物组研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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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
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2025
·Vol. 23
·期 1
·1-20
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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
Small
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2025
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IF 12.1
Tianao Xie,Yukai Shan,Win Topatana,Taorui Yang,Ruijing Shen,Shijie Li,Jiadong Chen,Yiyuan Zhu,Ziyi Lu,Yeling Liu,Tianen Chen,Yujie Gao,Yuchao Sun,Xiujun Cai,Sarun Juengpanich,Mingyu Chen
Hepatocellular carcinoma (HCC) is commonly classified as a “cold tumor” due to its low immunogenicity and poor response to conventional immunotherapies. Reprogramming the tumor immune microenvironment (TIME) via cuproptosis presents a promising strategy to enhance immunotherapies. Herein, sono-activatable N,N,N’,N’-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN)-encapsulated cancer-targeted nanoparticles (STCNs) designed to modulate the TIME and potentiate immunotherapy through endogenous cuproptosis are reported, termed “endogenous cuproptosis immunopromotion”. STCNs are rapidly internalized by HCC via folate-mediated endocytosis, and ultrasound irradiation triggers the release of TPEN. TPEN then chelates Cu 2 ⁺ from superoxide dismutase, initiating a Fenton-like reaction induced by glutathione that produces reactive oxygen species (ROS) and Cu⁺. This cascade induces cuproptosis and immunogenic cell death (ICD), promoting robust cytotoxic T lymphocyte infiltration in HCC. The combination of STCNs with anti-programmed cell death protein 1 (PD1) therapy demonstrates significant anti-tumor efficacy in vivo. Moreover, this strategy exhibits similar effectiveness in other solid tumor models, underscoring its broad therapeutic potential. These findings provide a promising framework for enhancing immunotherapy in cold tumors, paving the way for future cancer treatments.
研究领域:
肿瘤学
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免疫学
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纳米技术
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生物化学
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医学科学
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产品关联
DOI
PubMed
高影响因子
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
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2013
·Vol. 97
·期 17
·7597-7605
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IF 3.689
Xia Jun,Xu Hong,Feng Xiaohai,Xu Zhaoxian,Chi Bo
Poly(ε- l -lysine) (ε-PL) producer strain Streptomyces albulus PD-1 secreted a novel polymeric substance into its culture broth along with ε-PL. The polymeric substance was purified to homogeneity and identified. Matrix-assisted laser desorption ionization-time of flight mass spectrometry and nuclear magnetic resonance spectroscopy as well as other analytical techniques revealed that the substance was poly( l -diaminopropionic acid) (PDAP). PDAP is an l -α,β-diaminopropionic acid oligomer linking between amino and carboxylic acid functional groups. The molecular weight of PDAP ranged from 500 to 1500 Da, and no co-polymers composed of l -diaminopropionic acid and l -lysine were present in the culture broth. Compared with ε-PL, PDAP exhibited stronger inhibitory activities against yeasts but weaker activities against bacteria. ε-PL and PDAP co-production was also investigated. Both ε-PL and PDAP were synthesized during the stationary phase of growth, and the final ε-PL and PDAP concentration reached 21.7 and 4.8 g L -1 , respectively, in fed-batch fermentation. Citric acid feeding resulted in a maximum ε-PL concentration of 26.1 g L -1 and a decrease in the final concentration of PDAP to 3.8 g L -1 . No studies on ε-PL and PDAP co-production in Streptomyces albulus have been reported previously, and inhibition of by-products such as PDAP is potentially useful in ε-PL production.
研究领域:
微生物学
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生物化学
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分子生物学
✓ 已验证
DOI
高影响因子
Translational Oncology
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2026
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IF 4.9
Zhuo Chen,Meng-Lei Wang,Zhuo-Wen Zhang,Peng-Cheng Zhang,Qing-fang Yang,Yu-jing Weng,Jia-Long Shen,Wenxian Wang,Lan Shao
Background PD-1 blockade has become an important immunotherapeutic strategy, its clinical efficacy in non-small cell lung cancer (NSCLC) remains suboptimal. This study explores the effect and mechanism of sodium butyrate (NaB) and Clostridium butyricum ( C. butyricum ) combined with PD-1 inhibitors in NSCLC. Methods We established an NSCLC mouse model and evaluated tumor size, histopathology, apoptosis, cell proliferation, inflammatory factors, immune cell populations, and proteins of the HDAC1/ID2/IL-12R axis in the tumor, along with gut microbiome profiling. Results A combination of NaB or C. butyricum with PD-1 inhibitors significantly inhibited tumor growth and increased spleen and thymus indices. The combinations promoted tumor cell apoptosis, reduced the number of Ki67-positive proliferating cells, and increased IL-2, IL-6, IL-12, TNF-α, and IFN-γ levels in tumor tissues and serum. Additionally, the infiltration of CD4 + and CD8 + T cells in the tumor increased, while the Treg cells decreased. Importantly, the expressions of HDAC1 were markedly decreased, whereas ID2 and IL-12R levels increased in tumor tissues from NaB or C. butyricum with PD-1 inhibitor groups. Meanwhile, the combination of NaB or C. butyricum with PD‑1 inhibitors could alleviate the disturbance of gut microbiota by decreasing the Gordonibacter and increasing the WCHB1-32 . Significantly, the anti-CD8 antibody attenuated the inhibition of tumor growth conferred by NaB and PD‑1 inhibitors in vivo. Conclusions Collectively, NaB and C. butyricum enhanced the therapeutic action of PD‑1 inhibitors in murine models of NSCLC, possibly by modulating the HDAC1/ID2/IL-12R pathway, impacting intestinal microbiota and immune microenvironment.
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DOI
高影响因子
MATERIALS & DESIGN
·
2026
·
IF 8.2
Ruilin Ding,Hai Lin,Yinying Wu,Xuyuan Dong,Yangwei Fan,Longxia Chen,Gaochen Lan,Yu Shi,Meichen Wang,Enxiao Li
Virus-mimetic hollow Gd-Fe nanocarriers enable co-delivery of cisplatin and TGF-βRI inhibitor for synergistic chemo-ferroptosis therapy. • The nanoparticle trigger iron-dependent cell death while blocking TGF-β signaling, synergistically suppressing tumor growth. • The nanoparticle overcomes resistance to immune checkpoint therapy by shifting the tumor microenvironment toward an immune-active state. Ovarian carcinoma remains poorly responsive to immune checkpoint blockade, partly because of a TGF-β-enriched and immunosuppressive tumor microenvironment. Here, we developed a virus-mimetic hollow Gd-Fe nanocarrier for the co-delivery of cisplatin (DDP) and the TGF-β receptor I inhibitor TGFβRI-IN-3 (IN-3), aiming to integrate chemotherapy, ferroptosis induction, and TGF-β pathway blockade into a single therapeutic platform. DDP/IN-3@Gd-Fe nanoparticles (NPs) were prepared using a hard-template strategy. Cellular uptake, cytotoxicity, apoptosis, and ferroptosis-associated biochemical changes were evaluated in SKOV3 cells. In tumor-bearing mice, biodistribution, T1-weighted MRI contrast, biosafety, and antitumor efficacy were further investigated. The prepared NPs exhibited uniform size, good stability, and high drug loading with sustained release. In vitro , DDP/IN-3@Gd-Fe NPs were effectively internalized by SKOV3 cells and demonstrated superior cytotoxicity, apoptosis induction, and ferroptosis promotion compared to free drugs. In vivo , DDP/IN-3@Gd-Fe NPs exhibited the strongest tumor growth inhibition, involving synergistic induction of apoptosis and ferroptosis and effective suppression of the TGF-β signaling pathway. Finally, DDP/IN-3@Gd-Fe NPs were found to remodel the immunosuppressive TME by increasing inflammatory mediators and promoting tumor infiltration of cytotoxic T cells and dendritic cells. In conclusion, DDP/IN-3@Gd-Fe NPs provide an MRI-traceable chemo-ferroptosis platform that may attenuate TGF-β-associated immunosuppression and improve checkpoint blockade responses in ovarian carcinoma. Download: Download high-res image (168KB) Download: Download full-size image
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高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2021
·
IF 7.446
Yiqiang OuYang,Jian Gao,Lei Zhao,Junfeng Lu,Haiqing Zhong,Hua Tang,Shuanglong Jin,Lu Yue,Yuezhen Li,Wenjie Guo,Qiang Xu,Yisheng Lai
Two series of novel o-(biphenyl-3-ylmethoxy)nitrophenyl compounds (A1–31 and B1–17) were designed as programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) inhibitors. All compounds showed significant inhibitory activity with IC50 values ranging from 2.7 to 87.4 nM except compound A17, and compound B2 displayed the best activity. Further experiments showed that B2 bound to the PD-L1 protein without obvious toxicity in Lewis lung carcinoma (LLC) cells. Furthermore, B2 significantly promoted interferon-gamma secretion in a dose-dependent manner in vitro and in vivo. Especially, B2 exhibited potent in vivo anticancer efficacy in an LLC-bearing allograft mouse model at a low dose of 5 mg/kg, which was more active than BMS-1018 (tumor growth inhibition rate: 48.5% vs 17.8%). A panel of immunohistochemistry and flow cytometry assays demonstrated that B2 effectively counteracted PD-1-induced immunosuppression in the tumor microenvironment, thereby triggering antitumor immunity. These results indicate that B2 is a promising PD-1/PD-L1 inhibitor worthy of further development.
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Jia Zhang,Chunyu Lai,Bin Li,Hui Wang,Haimeng Yan,Xuanwen Bao,Xuqi Sun,Haibo Zhang,Zhou Tong,Tao Wang,Weijia Fang,Xiaomeng Dai,Peng Zhao,Dong Chen
Immune checkpoint blockade (ICB) therapies, such as targeting programmed death-1 (PD-1) and programmed cell death protein ligand-1 (PD-L1), are often ineffective in low-immunogenic tumors, limiting their widespread use. In this study, an emulsion hydrogel is developed to encapsulate the sonosensitizer hematoporphyrin monomethyl ether (HMME), aimed at enhancing sonodynamic immunotherapy for low-immunogenic cancers. The water-in-oil emulsion hydrogel, characterized by its shear-thinning rheological properties, demonstrates excellent ultrasound (US)-triggered and lipase-triggered release, followed by sustained release. The emulsion hydrogel loaded with HMME (Gel@HMME), when combined with US, induces an immune response by promoting dendritic cell (DC) maturation and M1-tumor-associated macrophage (M1-TAM) polarization. This, in turn, enhances the infiltration of helper T lymphocyte 1 (Th1) cells and cytotoxic T lymphocytes (CTLs), thereby amplifying the antitumor immune response. Furthermore, Gel@HMME + US enhances the expression of PD-L1 in tumor cells. The combination of ICB (anti-PD-1, αPD-1) with Gel@HMME + US exerts a significant therapeutic effect on pancreatic cancer by upregulating the expression of calreticulin. Thus, this study presents a promising strategy for treating low-immunogenic cancers using an injectable HMME-loaded emulsion hydrogel, which enhances sonodynamic immunotherapy.
研究领域:
生物材料
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癌症免疫治疗
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药物递送
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声动力治疗
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
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2025
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IF 10.2
Weiting Jiang,Wei Deng,Qi Chen,Huahua Zhang,Min Zhu,Rongze Wang,Yong Wang
Pancreatic cancers are marked by a highly fibrotic extracellular matrix (ECM) that fosters an immunosuppressive tumor microenvironment (TME), severely limiting the effectiveness of traditional therapies. Emerging evidence suggests that ECM modulation represents a promising strategy to enhance treatment outcomes in pancreatic cancer. Herein, we developed a polymeric nanovesicle for the co-encapsulation and delivery of gemcitabine and prolyl isomerase Pin1 inhibitor sulfopin (Gem/Sul-NP). The engineered Gem/Sul-NP features a compact size of approximately 50 nm, facilitating improved accumulation and penetration within pancreatic tumor tissues. Additionally, the Gem/Sul-NP demonstrates pH-responsive characteristics, undergoing structural disintegration at the acidic pH of 6.5 to achieve controlled drug release in the TME, thereby facilitating synergistic antitumor effects. Sulfopin functions to inhibit pancreatic stellate cells (PSCs) activation, reducing ECM component secretion and disrupting stromal barriers. Besides, it upregulates the expression of the gemcitabine transporter equilibrative nucleoside transporter 1 (ENT1) on tumor cell membranes, thereby enhancing the cellular uptake of gemcitabine and its chemotherapeutic impact. Our in vivo studies confirmed that Gem/Sul-NP treatment effectively remodeled the immunosuppressive TME. When combined with anti-PD-1 therapy, this approach significantly increased CD8 + IFNγ + T cell infiltration, indicating its potential to create favorable conditions for synergistic chemoimmunotherapy against pancreatic cancers.
研究领域:
肿瘤学
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纳米技术
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药剂学
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免疫学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2020
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IF 7.097
Lingyan Zhang,Mifang Li,Quan Zhou,Meng Dang,Yuxia Tang,Shouju Wang,Jijun Fu,Zhaogang Teng,Guangming Lu
Photodynamic therapy (PDT) has been widely used in cancer treatment. However, hypoxia in most solid tumors seriously restricts the efficacy of PDT. To improve the hypoxic microenvironment, we designed a novel mesoporous platinum (mPt) nanoplatform to catalyze hydrogen peroxide (H 2 O 2 ) within the tumor cells in situ without an extra enzyme. During the fabrication, the carboxy terminus of the photosensitizer chlorin e6 (Ce6) was connected to the amino terminus of the bifunctional mercaptoaminopolyglycol (SH-PEG-NH 2 ) by a condensation reaction, and then PEG-Ce6 was modified onto the mPt moiety via the mercapto terminal of SH-PEG-NH 2 . Material, cellular and animal experiments demonstrated that [email protected] catalyzed H 2 O 2 to produce oxygen (O 2 ) and that Ce6 transformed O 2 to generate reactive oxygen species (ROS) upon laser irradiation. The [email protected] nanoplatform with uniform diameter presented good biocompatibility and efficient tumor accumulation. Due to the high atomic number and good near-infrared absorption for Pt, this [email protected] nanoplatform showed computed tomography (CT) and photoacoustic (PA) dual-mode imaging ability, thus providing an important tool for monitoring the tumor hypoxic microenvironment. Moreover, the [email protected] nanoplatform reduced the expression of hypoxia-inducible factor-1 α (HIF-1 α ) and programmed death-1 (PD-1) in tumors, discussing the relationship between hypoxia, PD-1, and PDT for the first time.
研究领域:
癌症研究
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纳米技术
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生物医学工程
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成像技术
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治疗方法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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