International Journal of Nanomedicine
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2024
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IF 6.6
Haishui Sun,Xiao Wang,Zhaoyang Guo,Zhenrong Hu,Yuanchen Yin,Shuhan Duan,Wenwen Jia,Wei Lu,Jingzhou Hu
Introduction Traditional surgical resection, radiotherapy, and chemotherapy have been the treatment options for patients with head and neck squamous cell carcinoma (HNSCC) over the past few decades. Nevertheless, the five-year survival rate for patients has remained essentially unchanged, and research into treatments has been relatively stagnant. The combined application of photothermal therapy (PTT) and immunotherapy for treating HNSCC has considerable potential.Methods Live-dead cell staining and CCK-8 assays proved that Fe3O4 nanoparticles are biocompatible in vitro. In vitro, cellular experiments utilized flow cytometry and immunofluorescence staining to verify the effect of Fe3O4 nanoparticles on the polarisation of tumor-associated macrophages. In vivo, animal experiments were conducted to assess the inhibitory effect of Fe3O4 nanoparticles on tumor proliferation under the photothermal effect in conjunction with BMS-1. Tumour tissue sections were stained to observe the effects of apoptosis and the inhibition of tumor cell proliferation. The histological damage to animal organs was analyzed by hematoxylin and eosin (H&E) staining.Results The stable photothermal properties of Fe3O4 nanoparticles were validated by in vitro cellular and in vivo animal experiments. Fe3O4 photothermal action not only directly triggered immunogenic cell death (ICD) and enhanced the immunogenicity of the tumor microenvironment but also regulated the expression of tumor-associated macrophages (TAMs), up-regulating CD86 and down-regulating CD206 to inhibit tumor growth. The PD-1/PD-L1 inhibitor promoted tumor suppression, and reduced tumor recurrence and metastasis. In vivo studies demonstrated that the photothermal action exhibited a synergistic effect when combined with immunotherapy, resulting in significant suppression of primary tumors and an extension of survival.Conclusion In this study, we applied Fe3O4 photothermolysis in a biomedical context, combining photothermolysis with immunotherapy, exploring a novel pathway for treating HNSCC and providing a new strategy for effectively treating HNSCC.
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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
Cai Hai,Xue Panpan,Liu Siyuan,Ma Yaxin,Zeng Xuemei,Yan Shuangqian,Xu Ning
Elevated squalene epoxidase (SQLE) levels in bladder cancer cells drive abnormal cholesterol accumulation, contributing to malignancy, invasion, and resistance to immunotherapy. Here, we introduce a hollow CuO nanoparticle-based nanotherapeutic, termed CuOTeDsP, which is PEGylated and co-loaded with SQLE inhibitor terbinafine and disulfiram, for enhanced bladder cancer therapy through cholesterol metabolism modulation. CuO nanoparticles exhibit peroxidase-, catalase-, and glutathione oxidase-like enzymatic activities, along with biodegradability, resulting in elevated oxidative stress, alleviation of hypoxia, and responsive therapeutic release. Terbinafine reduces cholesterol levels in cancer cells by inhibiting SQLE, downregulating the expression of ATP7A and PD-L1, thereby promoting cellular Cu 2+ accumulation and enhancing immune responses. Disulfiram further reacts with Cu 2+ to form lethal bis(diethyldithiocarbamate)-copper complexes. Mechanistic studies reveal that CuOTeDsP induces cell death through a combination of cuproptosis and apoptosis, while simultaneously eliciting robust immune responses. In synergy with PD-1 monoclonal antibody, CuOTeDsP achieves a high tumor inhibition rate of 70% in a mouse bladder cancer model. This work highlights an effective strategy for bladder cancer by leveraging cuproptosis-driven immunotherapy and provides insights into the design of advanced nanotherapeutics.
Section
Graphical abstract
研究领域:
纳米医学
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癌症生物学
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免疫学
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代谢疾病
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药学
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npj Vaccines
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2025
·Vol. 10
·期 1
·1-13
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IF 6.5
Zhao Xingyang,Xuan Feichao,Li Zirong,Yin Xiangyi,Zeng Xiaojun,Chen Jiali,Fang Chihua
Hepatocellular carcinoma (HCC) is a highly prevalent malignancy with limited treatment efficacy despite advances in immune checkpoint blockade (ICB) therapy. The inherently weak immune responses in HCC necessitate novel strategies to improve anti-tumor immunity and synergize with ICB therapy. Kinesin family member 20A (KIF20A) is a tumor-associated antigen (TAA) overexpressed in HCC, and it could be a promising target for vaccine development. This study confirmed KIF20A as a promising immunogenic antigen through transcriptomic mRNA sequencing analysis in the context of HCC. Therefore, we developed a thermosensitive hydrogel vaccine formulation (K/R Lip @Gel) to optimize antigen delivery while enabling sustained in vivo release. The vaccine efficiently elicited robust immune responses by activating DCs and T cells. Moreover, K/R Lip @Gel improved the therapeutic efficacy of PD-L1 blockade in subcutaneous and orthotopic cell-derived xenograft (CDX) models, along with immune-humanized patient-derived xenograft (PDX) HCC models, which was evidenced by improved maturation of DCs and elevated infiltration and activation of CD8 + T cells. These findings highlight the potential of KIF20A-based vaccines to synergistically improve ICB therapy outcomes in HCC, providing a promising approach for enhancing anti-tumor immunity and improving clinical outcomes.
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
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PubMed
高影响因子
MOLECULAR THERAPY
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2024
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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
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-13
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IF 9.429
Gu Jun,Zhao Gang,Yu Jiangkun,Xu Pei,Yan Jiabin,Jin Zhengshuai,Chen Sheng,Wang Yong,Zhang Leshuai W.,Wang Yangyun
Although combination chemoimmunotherapy shows promising clinical results for cancer treatment, this approach is largely restricted by variable objective response rate and severe systemic adverse effects of immunotherapeutic antibody and chemotherapeutic drugs. Therefore, an in situ-formed therapeutic silk-chitosan composite scaffold is fabricated in this study to allow local release of the chemotherapeutic drug doxorubicin (DOX) and JQ1 (small molecular inhibitor used for the extraterminal protein BRD4 and bromodomain) with control release kinetics. DOX-JQ1@Gel contains a pH-degradable group that releases therapeutics in a weak acidic tumor microenvironment. The released DOX could directly kill tumor cells or lead to immunogenic cell death, thereby triggering the response of antitumor immunity. Meanwhile, chemotherapy-triggered antigen release and JQ1-mediated PD-L1 checkpoint blockade cumulatively contribute to trigger the response of antitumor immunity. Finally, the DOX-JQ1@Gel is locally injected to evaluate its synergistic cancer therapeutic effect, which is expected to improve objective response rate of immunotherapy and minimize systemic side effects.Graphical Abstract
研究领域:
癌症治疗
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药学
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生物材料
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免疫学
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PubMed
高影响因子
3 Biotech
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2026
·Vol. 16
·期 8
·328
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IF 3.1
Zhu Hengzhou,Zhu Xiaodan,Huang Xiaona,Qian Yiyang,Li Jiahui,Zhang Jiaying,Niu Dong,Jin Chunhui
Gastric cancer (GC) is a prevalent malignancy worldwide with high morbidity and mortality. Its insidious onset and lack of sensitive early biomarkers impede routine screening, so most patients present advanced or metastatic disease at first diagnosis, leading to poor prognosis and scarce curative options. Surgery, chemotherapy and targeted therapy serve as standard GC treatments, however their efficacy is restricted by metastasis, adverse reactions and drug resistance, which drives the rapid development of immune checkpoint inhibitor (ICI)-based immunotherapy. Although monoclonal antibodies targeting programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) resulted in significant survival benefits for GC patients, some patients exhibited an ineffective response. Our previous study has shown that Weitiao No. 3 (WD-3) enhanced the efficacy of anti-PD-1 immunotherapy by regulating intestinal flora in gastric cancer (GC) mice, in this study, huPBMC-NOG-dKO mice and MGC803 cells were used for in vivo and in vitro functional validation to explore the regulatory mechanism of WD-3 in GC immunotherapy. 16 S rRNA sequencing analysis of mouse fecal samples demonstrated that WD-3 significantly enriched the intestinal abundance of Lachnospiraceae and Ruminococcaceae in GC model mice. Targeted serum metabolomics further verified that WD-3 markedly elevated serum isobutyric acid level in GC mice. Combined with HE staining and tumor growth monitoring, both the intestinal flora mixture consisting of Lachnospiraceae and Ruminococcaceae and isobutyric acid prominently enhanced the anti-tumor efficacy of PD-L1 inhibitors in GC mice. Mechanistically, RNA sequencing and qRT-PCR assays identified ACOX2 as the most significantly up-regulated gene in isobutyric acid-treated MGC803 cells. Functional experiments using CCK-8 assay and flow cytometry revealed that isobutyric acid inhibited the viability and induced apoptosis of MGC803 cells, and such phenotypic changes were effectively rescued by ACOX2 knockdown. Furthermore, results from the CytoTox 96 cytotoxicity assay and ELISA revealed that combined treatment with isobutyric acid and PD-L1 inhibitor elevated the levels of LDH, IL-2, TNF-α, IFN-γ, Perforin 1 and GzmB, while suppressing IL-8, PD-1 and TIM-3 expression in CD8⁺ T cells co-cultured with MGC803 cells. Notably, all these regulatory effects were abrogated when MGC803 cells were transfected with si-ACOX2. These results suggested that WD-3 modulated intestinal flora to elevate isobutyric acid level, thereby enhancing the inhibitory effect of PD-L1 inhibitor on tumor growth and boosting the anti-tumor activity of CD8⁺ T cells by up-regulating ACOX2 expression in GC. These findings may provide novel targets for improving anti-PD-L1 therapy against GC.
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Natural Products and Bioprospecting
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2025
·Vol. 15
·期 1
·1-17
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IF 4.9
Zhao Huimin,Wang Yuyang,Liu Zining,Lin Lin,Xiang Jiasi,Zhu Zihao,Yang Xiongli,Fang Yongsheng,Kong Lingmei,Li Yan
Natural product tanshinone I exhibits weak potency and poor drug-like properties, which have restricted its clinical development as an anticancer agent. Herein, twenty novel tanshinone I-pyridinium salt derivatives and a pyridinium salt precursor were designed and synthesized, and their antitumor activities were evaluated. Among these tanshinone I-pyridinium salts, compound a4 , bearing a 4-bromobenzoylmethyl substituent at the N -1 position of the pyridine ring, showed the most potent cytotoxicity against breast cancer (MDA-MB-231), hepatocellular carcinoma (HepG2), and prostate cancer (22RV1) cell lines, with IC 50 values of 1.40–1.63 μM. Preliminary mechanistic studies suggest that a4 targets PI3Kα with the IC 50 of 9.24 ± 0.20 μM and exerts effective inhibition of the phosphorylation of key PI3K/Akt/mTOR signaling proteins. Besides, a4 significantly downregulates the expression of the immune checkpoint protein PD-L1, indicating its potential to activate tumor immunity. These findings demonstrate that tanshinone I-pyridinium salt derivative a4 is a novel PI3Kα inhibitor, providing a solid foundation for further development of antitumor agents. Graphical
研究领域:
药物化学
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肿瘤学
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药理学
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药物设计
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天然产物研究
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PubMed
高影响因子
ADVANCED MATERIALS
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2025
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IF 26.8
Yinghao Ding,Xueying Zhu,Jian Wen,Junchao Xiong,Shengyi Zhang,Zhimou Yang,Zhi-Wen Hu
Antigen presentation deficiency restricted by class I major histocompatibility complex (MHC-I) causes low antigenicity and antigen escape in tumors, thereby limiting T-cell immunotherapy outcomes. Here, a combined tumor immunotherapy is developed, in which tumors can present exogenous non-tumor antigens, and adoptively transferred CD8 + T cells specific for these antigens are re-targeted to attack tumors. The approach leverages a cascade-responsive peptide self-assembly to co-deliver suitable antigens and the chemotherapeutic drug camptothecin (CPT) to tumors. As a proof-of-concept, to re-target ovalbumin (OVA)-specific OT-I CD8 + T cells against tumors, PSA (Nap-GFFpYE-ss-Ag) and CPSA (CPT-GFFpYE-ss-Ag) are constructed, containing an OVA-derived epitope OVA 257-264 and/or CPT. The design enables the release of a unique N-terminal extended OVA 257-264 and CPT into the cytosol. As a result, the extended antigen is efficiently presented on the tumor surface by MHC-I, and CPT further enhances this presentation. When combined with adoptively transferred OT-I CD8 + T cells, the approach effectively facilitates CD8 + T cell infiltration and tumor inhibition. Additionally, CPSA treatment sensitizes immune responses to programmed cell death-ligand 1 (PD-L1) blockade, allowing the approach to synergize with an anti-PD-L1 antibody for improved tumor eradication.
研究领域:
肿瘤免疫学
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纳米医学
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药物递送系统
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免疫治疗
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分子自组装
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PubMed
高影响因子
Biomaterials Research
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2022
·Vol. 26
·期 1
·1-21
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IF 15.863
Wu Hao,Wei Guoli,Luo Lixia,Li Lingchang,Gao Yibo,Tan Xiaobin,Wang Sen,Chang Haoxiao,Liu Yuxi,Wei Yingjie,Song Jie,Zhang Zhenhai,Huo Jiege
Background Combination of chemotherapy and immune checkpoint inhibitor therapy has greatly improved the anticancer effect on multiple malignancies. However, the efficiency on triple-negative breast cancer (TNBC) is limited, since most patients bear “cold” tumors with low tumor immunogenicity. Doxorubicin (DOX), one of the most effective chemotherapy agents, can induce immunogenic cell death (ICD) and thus initiating immune response.Methods In this study, to maximize the ICD effect induced by DOX, chitosan and cell-penetrating peptide (R6F3)-modified nanoparticles (PNPs) loaded with ginsenoside Rg3 (Rg3) were fabricated using the self-assembly technique, followed by co-encapsulation with DOX based on thermo-sensitive hydrogel. Orthotopic tumor model and contralateral tumor model were established to observe the antitumor efficacy of the thermo-sensitive hydrogel combined with anti-PD-L1 immunotherapy, besides, the biocompatibility was also evaluated by histopathological.Results Rg3-PNPs strengthened the immunogenic cell death (ICD) effect induced by DOX. Moreover, the hydrogel co-loading Rg3-PNPs and DOX provoked stronger immune response in originally nonimmunogenic 4T1 tumors than DOX monotherapy. Following combination with PD-L1 blocking, substantial antitumor effect was achieved due to the recruitment of memory T cells and the decline of adaptive PD-L1 enrichment.Conclusion The hydrogel encapsulating DOX and highly permeable Rg3-PNPs provided an efficient strategy for remodeling immunosuppressive tumor microenvironment and converting immune “cold” 4T1 into “hot” tumors.
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BIOSENSORS & BIOELECTRONICS
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2025
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IF 10.5
Yuping Liu,Beibei Zhang,Xueyuan Wu,Fan Wang,Zhiyi Yang,Mengyi Li,Kaixuan Sheng,Yue Yan,Liang Zhu,Hui Jing,Yanmin Wu,Lili Hu,Yanyan Yu,Chenglin Li
Programmed cell death 1 ligand 1 (PD-L1) immunotherapy holds a pivotal role in lung cancer treatment. However, current methods for monitoring PD-L1 expression exhibit several limitations, including hysteresis and the invasive nature of tissue sampling. Circulating tumor cells (CTCs), the important biomarkers in liquid biopsy, are minimally invasive and facilitate continuous monitoring. Consequently, integrating CTC counting with PD-L1 expression analysis offers more comprehensive insights for the development of personalized treatment strategies development and efficacy evaluations. In this study, we presented a facile liquid biopsy assay designed for the dynamic monitoring of PD-L1 expression on CTCs captured from non-small cell lung cancer (NSCLC) patients. This assay was achieved by fabricating two high-performance probes: EpCAM and Vimentin dual-aptamer modified nitrogen-doped carbon quantum dots probe (E/V-apt-N-CQDs) and hairpin PD-L1 aptamer coupled with gold nanoparticles (PD-L1-apt-AuNPs). The E/V-apt-N-CQDs probe effectively captured two types of CTC models (H1299 and A549) exhibiting differential PD-L1 expression. Additionally, reagent-less detection of PD-L1 levels on CTCs was achieved using a portable magnetic electrochemical sensor with excellent specificity and sensitivity, which was capable of measuring PD-L1 concentrations as low as 2 ng/mL. Finally, this assay was applied in 41 NSCLC patients to investigate the correlation between CTC numbers or PD-L1 expression and disease progression and immunotherapy efficacy. The results indicated a significant association between elevated CTC counts or reduced PD-L1 levels and clinical progression. Moreover, this liquid assay successfully monitored dynamic changes in CTCs and PD-L1 expression in NSCLC patients receiving immunotherapy, indicating its potential for clinical application.
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Advanced Science
·
2024
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IF 14.3
Zaigang Zhou,Cheng Li,Chao Li,Lei Zhou,Shuo Tan,Weibin Hou,Congying Xie,Long Wang,Jianliang Shen,Wei Xiong
It is newly revealed that collagen works as a physical barrier to tumor immune infiltration, oxygen perfusion, and immune depressor in solid tumors. Meanwhile, after radiotherapy (RT), the programmed death ligand-1 (PD-L1) overexpression and transforming growth factor-β (TGF-β) excessive secretion would accelerate DNA damage repair and trigger T cell exclusion to limit RT efficacy. However, existing drugs or nanoparticles can hardly address these obstacles of highly effective RT simultaneously, effectively, and easily. In this study, it is revealed that inducing mitochondria dysfunction by using oxidative phosphorylation inhibitors like Lonidamine (LND) can serve as a highly effective multi-immune pathway regulation strategy through PD-L1, collagen, and TGF-β co-depression. Then, IR-LND is prepared by combining the mitochondria-targeted molecule IR-68 with LND, which then is loaded with liposomes (Lip) to create IR-LND@Lip nanoadjuvants. By doing this, IR-LND@Lip more effectively sensitizes RT by generating more DNA damage and transforming cold tumors into hot ones through immune activation by PD-L1, collagen, and TGF-β co-inhibition. In conclusion, the combined treatment of RT and IR-LND@Lip ultimately almost completely suppressed the growth of bladder tumors and breast tumors.
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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放射生物学
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
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IF 13.3
Han Yan,Wenting Cheng,Siyuan Qin,Jing Zuo,Lei Li,Jing Zhang,Qinxia Chang,Yonghao Yan,Shiqi Wang,Canhua Huang,Haiyuan Zhang
The blood–brain barrier (BBB) caused limited drug accumulation and programmed death-ligand 1 (PD-L1) compromised immunosuppressive microenvironment are bottlenecks in glioblastoma multiforme (GBM) treatment. Herein, we bioengineered a human heavy chain nanoferritin (HTE NPs) for GBM-specific delivery and efficient immunotherapy. To achieve targeted mitochondrial metabolic regulation, we connected triphenylphosphonium (TPP) with the photosensitive agent IR780 to form T780, which self-assembles with esomeprazole magnesium (EM) and human H-ferritin (HFn) to obtain HTE NPs. HFn endows HTE NPs with BBB penetration and specific site-targeting capabilities, thereby enhancing tumor accumulation and pH-responsive release within GBM cells. T780 subsequently induces mitochondrial damage, activating the AMP-dependent protein kinase (AMPK) pathway and blocking the transmission of T-cell inhibitory signals through the phosphorylation of PD-L1, thereby promoting T-cell activation. Moreover, EM inhibits the release of extracellular vesicles (EVs), reducing the inhibitory effect of PD-L1 on circulating T cells. Furthermore, mitochondrial impairment-induced mitochondrial DNA (mtDNA) leakage activates the cGAS-STING signaling pathway, inducing the maturation of dendritic cells (DCs), recruiting supportive immune cells to clear GBM cells, and improving the immunosuppressive microenvironment. Therefore, HTE NPs not only achieve efficient tumor accumulation but also facilitate the activation immune response, providing a promising strategy for the clinical treatment of GBM.
研究领域:
肿瘤学
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神经科学
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纳米技术
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免疫学
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高影响因子
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