BIOMATERIALS
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2025
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IF 12.9
Hui Zhi,Weimin Yin,Shiyu Chen,Xiaoyou Zhang,Zichen Yang,Fulong Man,Rongjie Li,Yanni Cai,Yang Li,Caoyi You,Yan Li,Yongyong Li,Haiqing Dong
Cuproptosis and ferroptosis exhibit superior synergistic advantages in antitumor therapy. While glutathione (GSH) has been identified as a key molecule in enhancing the synergistic effects of these two processes, inherent cellular redox homeostasis mechanisms limit its therapeutic efficacy. This inspired us to explore other new regulators to potentiate the synergistic effect. Through bioinformatics analysis and preliminary experimental validation, we discovered that lactate metabolism is closely associated with both ferroptosis and cuproptosis. Therefore, this work strategically targets lactate metabolism to synergistically activate cuproptosis and ferroptosis, and elucidate its immunotherapeutic mechanisms. For this purpose, we constructed a Syr-loaded nanodelivery system (Syr@mPDA@CP) using biocompatible mesoporous polydopamine (mPDA) as the carrier. Upon targeted to tumor tissues, the released Syr significantly inhibits lactate efflux, leading to intracellular lactate accumulation. This lactate buildup further induces intracellular acidification, exerting dual effects: (1) promoting ferritin (FTH1) dissociation to release endogenous iron stores, thereby elevating intracellular iron levels; and (2) suppressing glycolysis and reducing ATP levels, which inactivates the copper export protein ATP7B. Combined with copper peroxide (CP)-derived Cu 2+ , these effects synergistically amplify intracellular copper accumulation. The elevated intracellular Cu and Fe concentrations subsequently induce dual cell death pathways of cuproptosis and ferroptosis, effectively enhancing cancer immunotherapy. This study pioneers a lactate metabolism-regulating strategy to synergistically amplify both ferroptosis and cuproptosis, offering novel perspectives for antitumor therapy.
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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生物化学
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产品关联
DOI
PubMed
高影响因子
Materials Horizons
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2025
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IF 10.7
Jieying Zhang,Pengrui Wang,Lingkai Meng,Xiaohe Li,Fang Li,Na Kong,Xingjun Zhu
Emerging immunotherapies have demonstrated remarkable potential in cancer treatment. However, persistent challenges including insufficient immune activation and limited tumor infiltration remain unresolved. Here, we introduce focused-ultrasound (FUS) responsive artificial killer cells (AKCs), a novel biomimetic system integrating functions of natural killer (NK) cells, dendritic cells (DCs) and macrophages for closed-loop tumor immunotherapy. AKCs consist of lanthanide nanoparticles integrated within a hybrid lipid membrane, which not only improves biocompatibility but also enables real-time monitoring through near-infrared (NIR) imaging. Compared to traditional liposomal formulations, AKCs demonstrate superior tumor targeting and retention properties, significantly improving the reliability of diagnostics and therapeutic efficacy. The innovative use of FUS allows for controlled release of copper cations, which, in conjunction with the recruitment of dendritic cells via RANTES (Regulated on Activation, Normal T-cell Expressed and Secreted) cytokine release, transforms the immunosuppressive tumor microenvironment to immunologically active states. Cuproptosis induced by AKCs can significantly enhance tumor elimination efficacy. Tumor bearing mice exhibited prolonged survival and tumor regression with AKCs exhibiting superior tumor targeting and sustained antitumor effects. This research highlights a multifaceted approach to cancer immunotherapy, combining innate and adaptive immune activation mechanisms, thereby suggesting a promising direction for future advancements in targeted cancer therapies.
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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纳米技术
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Yu-Yi Ling,Qing-Hua Shen,Liang Hao,Zhi-Yuan Li,Long-Bo Yu,Xiao-Xiao Chen,Cai-Ping Tan
Being a recently identified mode of programmed cell demise, the functional implications of cuproptosis in the genesis, progression, and therapeutic modulation of cancer remain largely unknown. Given that cuproptosis is predominantly elicited by cellular copper overload, notably attributable to the dysregulation of copper homeostasis within mitochondria, we designed a series of phosphorescent rhenium(I) complexes (Re1–Re5) as suborganelle-targeted copper ionophores. Among them, Re5 can successfully transport extracellular copper into mitochondria and the Golgi apparatus and especially enrich copper into mitochondria. Consequently, Re5 breaks the cellular redox balance and disturbs the energetic and metabolism pathways to induce cuproptosis. Finally, we prove that Re5 can promote immune responses and modulate cancer immune microenvironments. In all, we present here the first subcellular organelle-targeted copper ionophore and prove that cuproptosis-inducing small molecules are potent cancer immunotherapeutic candidates.
研究领域:
生物化学
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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
Cancers
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2022
·Vol. 14
·期 23
·5951
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IF 6.575
Qiyi Yi,Youguang Pu,Fengmei Chao,Po Bian,Lei Lv
Simple SummaryACAP1 plays a key role in endocytic recycling, which is essential for the normal function of lymphocytes. This study aimed to assess the expression and function of ACAP1 in lymphocytes. In this study, we revealed that ACAP1 is expressed primarily in lymphocytes and is necessary for the normal function of lymphocytes. Its expression is regulated by promoter DNA methylation and the transcription factor SPI1. ACAP1 levels positively correlate with the infiltrating levels of tumor-infiltrating lymphocytes (TILs) across a broad range of solid cancer types. Moreover, ACAP1 deficiency is associated with poor prognosis and immunotherapeutic response in multiple cancer types treated with immunotherapy. Thus, this study demonstrates that ACAP1 is a novel lymphocyte marker. We propose a widely applicable indicator to predict response to immunotherapy that may guide cancer patient stratification for appropriate therapy.AbstractBackground: ACAP1 plays a key role in endocytic recycling, which is essential for the normal function of lymphocytes. However, the expression and function of ACAP1 in lymphocytes have rarely been studied. Methods: Large-scale genomic data, including multiple bulk RNA-sequencing datasets, single-cell sequencing datasets, and immunotherapy cohorts, were exploited to comprehensively characterize ACAP1 expression, regulation, and function. Gene set enrichment analysis (GSEA) was used to uncover the pathways associated with ACAP1 expression. Eight algorithms, including TIMER, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, xCELL, MCPCOUNTER, EPIC, and TIDE, were applied to estimate the infiltrating level of immune cells. Western blotting, qPCR, and ChIP-PCR were used to validate the findings from bioinformatic analyses. A T-cell co-culture killing assay was used to investigate the function of ACAP1 in lymphocytes. Results: ACAP1 was highly expressed in immune-related tissues and cells and minimally in other tissues. Moreover, single-cell sequencing analysis in tumor samples revealed that ACAP1 is expressed primarily in tumor-infiltrating lymphocytes (TILs), including T, B, and NK cells. ACAP1 expression is negatively regulated by promoter DNA methylation, with its promoter hypo-methylated in immune cells but hyper-methylated in other cells. Furthermore, SPI1 binds to the ACAP1 promoter and positively regulates its expression in immune cells. ACAP1 levels positively correlate with the infiltrating levels of TILs, especially CD8+ T cells, across a broad range of solid cancer types. ACAP1 deficiency is associated with poor prognosis and immunotherapeutic response in multiple cancer types treated with checkpoint blockade therapy (ICT). Functionally, the depletion of ACAP1 by RNA interference significantly impairs the T cell-mediated killing of tumor cells. Conclusions: Our study demonstrates that ACAP1 is essential for the normal function of TILs, and its deficiency indicates an immunologically “cold” status of tumors that are resistant to ICT.Keywords:ACAP1;tumor-infiltrating lymphocytes (TILs);immune checkpoint blockade therapy (ICT);cancer immunotherapy;CD8+ T cells
研究领域:
肿瘤学
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免疫学
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癌症生物学
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分子生物学
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基因组学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
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2019
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IF 2.431
Ning Wang,Jie Zhang,Qiao Li,Hui Xu,Geng Chen,Zhiyong Li,Difa Liu,Xin Yang
Indoleamine 2,3-dioxygenase (IDO) is one of the important targets for cancer immunotherapy through tryptophan pathway. Recently it has being paid great attention to search potent and safe IDO inhibitor from small-molecule compounds. Picrasma quassioides is a kind of medicinal plant abundant with tryptophan-derived indole alkaloids . By virtual screening and kinetic method for enzymatic analysis, lead compounds with potential IDO inhibitory activity were discovered for the first time from PQAs, the natural alkaloids in Picrasma quassioides . The results based on molecular docking analysis and structure-activity relationship (SAR) study demonstrated that coordinating with ferrous ion on the active site of IDO has a great impact on the inhibition potency, and β -carboline with carboxyl substituted on C-1 is the key pharmacophore for IDO inhibition of PQAs. Enzymatic assay provided further evidence for the effectiveness of β -carboline-1-carboxylic acid, which displayed as the most potent competitive inhibitor of IDO among these PQAs, and is even more potent than the recognized positive control 1-methyl tryptophan. This natural tryptophan-derived alkaloid thus deserved further deep research as a promising IDO modulator for cancer immunotherapy.
研究领域:
药理学
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肿瘤学
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植物化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2021
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IF 6.953
Ye Yang,Tingting Guo,Junwei Xu,Yin Xiong,Xiuming Cui,Yang Ke,Chengxiao Wang
Here, we fabricated amphiphilic polysaccharide micelles for synergistic cancer immunotherapy targeting tumor-associated macrophages (TAMs). Lepidium meyenii Walp. (maca) polysaccharide (MP), a naturally derived macromolecule with a strong TAM-remodeling effect, was grafted on a hydrophobic poly(lactic- co -glycolic acid) (PLGA) segment, with a disulfide bond for redox-sensitive linkage. The amphiphilic polysaccharide derivatives could self-assemble into core (PLGA)–shell (MP)-structured micelles and encapsulate chloroquine (CQ) into the hydrophobic core. By using a 4T1-M2 macrophage co-culture model and a 4T1 tumor xenograft mouse model, we showed that the prepared micelles could co-deliver MP and CQ to the tumor sites and selectively accumulate at TAMs because of the specific properties of MP. Furthermore, the nanoparticles exerted synergistic tumor immunotherapeutic and antimetastatic effects, which might be attributable to the enhanced cell internalization of the micelles and the multiple regulatory mechanisms of MP and CQ. Thus, immunomodulatory MP may be a promising biomaterial for cancer immunotherapy.
研究领域:
纳米技术
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药学
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免疫学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2023
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IF 8
Fang Huang,Jinjin Zhao,Yiting Wei,Zhifa Wen,Yue Zhang,Xuru Wang,Yanfei Shen,Li-xin Wang,Ning Pan
Background and Aim We have previously identified ubiquitinated proteins (UPs) from tumor cell lysates as a promising vaccine for cancer immunotherapy in different mouse tumor models. In this study, we aimed at developing a highly efficient therapeutic adjuvant built-in nanovaccine (α-Al2O3-UPs) by a simple method, in which UPs from tumor cells could be efficiently and conveniently enriched by α-Al2O3 nanoparticles covalently coupled with Vx3 proteins (α-Al2O3-CONH-Vx3).Methods The α-Al2O3 nanoparticles were modified with 4-hydroxybenzoic acid followed by coupling with ubiquitin-binding protein Vx3. It was then used to enrich UPs from 4T1 cell lysate. The stability and the efficiency for the UPs enrichment of α-Al2O3-CONH-Vx3 were examined. The ability of α-Al2O3-UPs to activate DCs was examined in vitro subsequently. The splenocytes from the vaccinated mice were re-stimulated with inactivated tumor cells, and the IFN-γ secretion was detected by ELISA and flow cytometry. Moreover, the therapeutic efficacy of α-Al2O3-UPs, alone and in combination with chemotherapy, was examined in 4T1 tumor-bearing mice.Results Our results showed that α-Al2O3-UPs were successfully synthesized and abundant UPs from tumor cell lysate were enriched by the new method. In vitro study showed that compared to the physical mixture of α-Al2O3 nanoparticles and UPs (α-Al2O3+UPs), α-Al2O3-UPs stimulation resulted in higher upregulations of CD80, CD86, MHC class I, and MHC class II on DCs, indicating the higher ability of DC activation. Moreover, α-Al2O3-UPs elicited a more effective immune response in mice, demonstrated by higher IFN-γ secretion than α-Al2O3+UPs. Furthermore, α-Al2O3-UPs also exhibited a more potent effect on tumor growth inhibition and survival prolongation in 4T1 tumor-bearing mice. Notably, when in combination with low dose chemotherapy, the anti-tumor effect was further enhanced, rather than using α-Al2O3-UPs alone.Conclusion This study presents an adjuvant built-in nanovaccine generated by a new simple method that can be potentially applied to cancer immunotherapy and lays the experimental foundation for future clinical application.
研究领域:
肿瘤学
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免疫学
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药学
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生物技术
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Qing-Hua Shen,Long-Bo Yu,Shan-Ming Yao,Zhi-Yuan Li,Qi-Qi Zhang,Peng Wang,Cai-Ping Tan
Metalloenzyme mimics based on small molecules are valuable therapeutic candidates, but there are few reports on their mechanism of action. Inspired by natural enzymes, we designed two Cu–Fe bimetallic multienzyme mimetics (CuFc1 and CuFc2). Due to the coordination of the bimetallic centers, CuFc1 exhibits mimetic activities for multiple enzymes, including peroxidase (POD), catalase (CAT), superoxide dismutase (SOD), and glutathione oxidase (GSHOx). CuFc1 can catalyze cascade reactions from •O2– and H2O2 to O2 and •OH, which leads to a storm of reactive oxygen species and causes cuproptosis and ferroptosis in cancer cells simultaneously. As CuFc1 treatment upregulates the expression of PD-L1, it acts synergistically with the PD-L1 inhibitor (BMS-1) to remodel the tumor immune microenvironments and stimulates intense anticancer immune responses in vivo. In summary, through reasonable molecular design, we first demonstrate the enormous potential of metallo small molecule-based multienzyme mimics in cancer immunotherapy.
研究领域:
生物无机化学
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癌症生物学
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免疫治疗
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酶学
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金属药物
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产品关联
DOI
PubMed
高影响因子
Science Advances
·
2020
·Vol. 6
·期 47
·
IF 13.117
Liyin Yu,Ruyan Feng,Lijuan Zhu,Qing Hao,Jiacheng Chu,Yan Gu,Yan Luo,Zexin Zhang,Gaojian Chen,Hong Chen
Dendritic cell (DC) modification to enhance antigen presentation is a valuable strategy in cancer immune therapy. Other than focusing on regulating interactions between DC and antigens, we intend to promote cell interactions between DC and T cell by cell surface engineering. T cell activation is greatly improved and generates higher tumor toxicity with the aid of the synthetic glycopolymer modified on the DC surface, although the glycopolymer alone shows no effect. The great promotion of DC–T cell attraction is revealed by cell image tracking in terms of both frequency and duration of contacts. Our findings provide a new method of T cell activation by these engineered “sweet DCs.” This strategy is beneficial for developing more efficient DC-based vaccines.
研究领域:
免疫学
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癌症研究
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2025
·
IF 4.8
Mengxue Zhou,Ying Wang,Hongchun Cui,Huan Geng,Lifo Ruan,Yanni Zhao,Chuang Zhou,Weidong Dai,Jun Chen,Jizhong Yu,Haipeng Lv,Zhi Lin
Enhancing cancer immunotherapy using methods that induce immunogenic cell death (ICD) can significantly improve its effectiveness and profoundly influence its role as a highly efficient cancer treatment strategy. However, the limited penetration of cytotoxic T cells into tumors, owing to dense tumor fibrosis, remains a significant barrier to immunotherapy. A tumor microenvironment-sensitive intelligent dual-drug delivery system was developed to simultaneously deliver epigallocatechin-3-gallate (EGCG) and doxorubicin (DOX) to mitochondria. EGCG enhanced the mitochondria-targeted action of DOX and increased damage to the mitochondrial electron transport chain which facilitated capturing electrons in the mitochondrial matrix of DOX. Subsequently, DOX molecules form a semiquinone intermediate and electrons are transferred to oxygen to generate reactive oxygen species (ROS) that induce mitochondrial apoptosis. These results indicate that EGCG amplifies the combined effects of chemo/chemodynamic therapy of DOX, demonstrating a pronounced synergistic ICD effect that recruits CD8+ T cells to the tumor microenvironment (TME). In addition, EGCG promotes T-cell infiltration into tumor tissues by inhibiting the transforming growth factor-β signaling pathway, thereby significantly enhancing antitumor efficacy. This study advances the efficacy of immunotherapy through bidirectional synergy, which not only enhances intrinsic tumor immunogenicity but also overcomes the extrinsic physical barriers of tumors, providing a new direction for the development of broadly applicable immunotherapies.
研究领域:
肿瘤学
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药理学
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生物医学工程
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免疫学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Xu Gui-Qing,Gong Xiao-Qing,Zhu Ying-Ying,Yao Xiao-Jun,Peng Li-Zeng,Sun Ge,Yang Jian-Xue,Mao Long-Fei
Indoleamine 2,3-dioxygenase 1 (IDO1) plays a predominant role in cancer immunotherapy which catalyzes the initial and rate limiting steps of the kynurenine pathway as a key enzyme. To explore novel IDO1 inhibitors, five derivatives of erlotinib-linked 1,2,3-triazole compounds were designed by using a structure-based drug design strategy. Drug-target interactions (DTI) were predicted by DeePurpose, an easy-to-use deep learning library that contains more than 50 algorithms. The DTI prediction results suggested that the designed molecules have potential inhibitory activities for IDO1. Chemical syntheses and bioassays showed that the compounds exhibited remarkable inhibitory activities against IDO1, among them, compound e was the most potent with an IC50 value of 0.32 ± 0.07 μM in the Hela cell assay. The docking model and ADME analysis exhibited that the effective interactions of these compounds with heme iron and better drug-likeness ensured the IDO1 inhibitory activities. The studies suggested that compound e was a novel and interesting IDO1 inhibitor for further development.
研究领域:
癌症研究
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药物化学
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药物设计
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生物信息学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
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IF 13.2
Haoqi Pan,Xiaoning Yu,Qing He,Lixia Yi,Mingming Xiao,He Xu,Qingcai Meng,Jie Hua,Dong Cen,Si Shi,Xianjun Yu
Advancements in nanobiotechnology have significantly augmented the efficacy of metallodrugs for cancer therapy. Additionally, gas therapies, including oxygen and nitric oxide, hold promise for tumor treatment due to their capacity to manipulate the tumor microenvironment (TME). Herein, we synthesized vanadium nitride (V 2 N) nanosheets (NSs) and converted them into quantum dots (QDs) via hydrothermal synthesis method. After modification with triphenylphosphine (TPP) and soybean phospholipids (SP), the V 2 N@TPP/SP QDs exhibited nanozyme-like activity and activated H 2 O 2 through nonradical pathways, demonstrating effective mitochondria-targeting capabilities. Upon degradation into vanadate, they inhibited Na + /K + ATPase and K + efflux, disrupting mitochondrial membrane potential, and triggering reactive oxygen species (ROS) induced ferroptosis. Furthermore, V 2 N@TPP/SP QDs served as nitric oxide (NO) gas donors, activating reactive nitrogen species (RNS) and enhancing immunogenic cell death (ICD) induction. Combined with α-PD-L1 immunotherapy, they synergistically augmented antitumor treatment by reversing immune suppression in the TME, thereby restraining tumor growth. Our research established a foundation for employing vanadium-based drugs and gas therapy in cancer treatment.
研究领域:
生物医学工程
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肿瘤学
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免疫学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）