JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Yali Wu,Wenjuan Chen,Jingjing Deng,Xingyu Zhou,Jiangbin Chen,Zimo Yang,Xinghui Cao,Jiatong Liu,Qi Tan,E. Zhou,Minglei Li,Mengfei Guo,Yang Jin
Cancer immunotherapy has transformed cancer treatment, demonstrating the potential for lasting responses in multiple solid and hematologic malignancies and thus has revolutionized cancer treatment in clinic. However, the intricate tumor microenvironment (TME), characterized by a rigid extracellular matrix (ECM) and robust immunosuppressive environment, presents substantial hurdles to the effectiveness of cancer immunotherapy. Thus, cancer-associated fibroblasts (CAFs), the most abundant stromal cells that mediate ECM remodeling and participate in immune suppression, represent promising therapeutic targets for combination immunotherapy. In this study, by using and analyzing single-cell RNA-sequencing (scRNA-seq) in the public datasets, we have identified the elevated expression of glucose transporter 1 (GLUT1) in activated CAF subgroups within tumor sites compared to normal tissues. Moreover, the recent literature has also demonstrated that CAFs undergoing high metabolic levels have been identified to show a better response to immunotherapy. Furthermore, extracellular vesicles (EVs) secreted by CAFs remain unexplored, and their role in drug transport systems and targeting efficiency towards tumorous cells remains uninvestigated. Herein, we identified the elevated expression of glucose transporter 1 (GLUT1) as a prognostic indicator for cancer associated with poor prognosis and investigated the vulnerability of lung tumor cell lines and CAFs to pharmacological GLUT1 inhibition with BAY-876. Based on the possibility of targeting the intrinsic TME-associated metabolism by GLUT1 inhibition, we have firstly employed CAFs-derived extracellular vesicles (cEVs) as a carrier for targeted delivery of BAY-876 into GLUT1-high CAFs and tumor cells. The cEV-BAY-876 (cEV B6) treatment significantly resulted in glucose-rich, low-lactate TME, reversed the activated CAFs phenotype, enabled stromal reprogramming, decreased ECM stiffness and enhanced the infiltration of CD3 + CD8+ T cells in tumor core, thereby achieving an excellent anti-tumor efficiency. Moreover, cEV-B6 treatment synergized anti-programmed death ligand 1 (antiPD-L1) to reinvigorate the exhausted lymphocytes and exerted strong anticancer effects against mice lung tumors. Our study provides the first evidence that tumor stroma-specific therapies by targeting glucose metabolism present a promising strategy of remodeling the extracellular matrix to reverse CAFs into normal type and potentiate cytotoxic T lymphocytes (CTLs) infiltration thereby improving anticancer immunotherapy.
研究领域:
肿瘤生物学
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免疫治疗
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代谢调控
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生物材料与递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-18
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IF 10.435
Zhao Bonan,Dong Zhipeng,Liu Weixing,Lou Fangning,Wang Qiyan,Hong Hao,Wang Yue
Background According to data estimated by the WHO, primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of death around the world. Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, so effective therapy is highly desired for HCC. Results In this study, the use of poly( l -Aspartic acid)-poly(ethylene glycol)/combretastatin A4 (CA4-NPs) was aimed to significantly disrupt new blood vessels in tumor tissues for targeted hepatic tumor therapy. Here, PEG-b-PAsp-g-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, CA4-NPs were mainly distributed at the tumor site because of the triple target effects—enhanced permeability and retention (EPR) effect, acid-sensitive (pH = 5.5) effect to the tumor microenvironment (TME), and good selectivity of CA4 for central tumor blood vessel. Considering that CA4-NPs might induce severe hypoxic conditions resulting in high expression of HIF-1α in tumor tissues, which could induce the overexpression of PD-L1, herein we also used a programmed death-ligand 1 antibody (aPD-L1) to prevent immunosuppression. This way of complementary combination is able to achieve an ideal treatment effect in tumor site where CA4-NPs and aPD-L1 could respond to the inner area and peripheral area, respectively. As a result, a significant decrease in tumor volume and weight was observed in the combination group of CA4-NPs plus aPD-L1 compared with CA4-NPs or aPD-L1 monotherapy in subcutaneous Hepa1-6 hepatic tumor models. Conclusions We presented a new idea that co-administration of CA4-NPs and aPD-L1 possessed notable anti-tumor efficacy for HCC treatment. Graphic abstract
研究领域:
肿瘤学
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药学
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免疫疗法
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2020
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IF 10.652
Ningning Wang,Yaxin Zhou,Yuwen Xu,Xiaomeng Ren,Shiyao Zhou,Qi Shang,Yue Jiang,Yuxia Luan
Immune checkpoint blockade (ICB) strategy based on suppressing programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has been proved to be promising and effective in cancer immunotherapy. However, its potential risk of immune-related adverse events (irAEs) places stringent requirements on the precise loading of anti-PD-L1 agent in nanomedicine. Precise control of the loading content of anti-PD-L1 antibody is a difficult task since physical encapsulation has inevitable drawbacks like batch-to-bath variation and chemical modification is limited by the low stability of the antibody. Herein, we proposed a molecular engineering strategy to develop the nanomedicine with precise control of anti-PD-L1 agent content by using anti-PD-L1 peptide (APP) as the substitute to anti-PD-L1 antibody. The APP was chemically bonded with a photosensitizer IR780 to obtain IR780-M-APP, a molecule able to self-assemble into nanoparticles (NPs) with a precise APP loading (48.4 wt%) determined by the molecular structure. Specifically, the IR780 moiety in IR780-M-APP NPs endows the nanoparticles with photodynamic therapeutic effect as well as the ability to trigger immunogenic cell death (ICD), while the APP moiety can block the PD-1/PD-L1 pathway for promoting immunotherapy. The proposed photodynamic-immunotherapy nanoplatform not only killed primary tumors directly but also eradicated the metastatic and invasive tumors effectively. The present molecular engineering strategy combined with anti-PD-L1 peptide might provide more opportunities for the design of advanced nanoplatforms for cancer therapy.
研究领域:
肿瘤学
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免疫学
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纳米医学
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分子工程
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产品关联
DOI
高影响因子
mSystems
·
2024
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IF 5
Lei Tang,Xizhong Yang,Mengting Zhou,Lingxin Feng,Cuijie Ji,Jie Liang,Bei Zhang,Ruowu Shen,Luoyang Wang
Growing evidence indicates that gut microbiota is involved in the regulation of the host’s sex hormone levels, such as through interfering with the sex hormone metabolism in the intestine. However, if gut microbiota or its metabolites directly influence the sex hormone biosynthesis in the gonad remains largely unknown. Our previous study showed that colistin, as a narrow-spectrum antibiotic, can significantly downregulate the serum testosterone levels and thus enhance the antitumor efficiency of anti-PD-L1 in male mice; however, the underlying mechanism for the regulation of the host’s testosterone levels remains uninvestigated. In the present study, we analyzed the impact of colistin on the immune microenvironment of the testis as well as the composition and metabolism of gut microbiota in male mice. Our results showed that colistin has an impact on the immune microenvironment of the testis and can downregulate serum testosterone levels in male mice through inhibition of Akkermansia, leading to destroyed inosine metabolism. Supplement with inosine can restore testosterone secretion probably by prompting the recovery of the intestinal mucus barrier and the serum lipopolysaccharides levels. All these findings reveal a new pathway for the regulation of the host’s sex hormone levels by gut microbiota.
研究领域:
微生物学
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免疫学
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内分泌学
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药理学
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DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 40
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IF 11.7
Naming Wu,Jun Li,Lu Li,Liu Yang,Liyun Dong,Chen Shen,Shanshan Sha,Yangxue Fu,Enzhu Dong,Fang Zheng,Zheng Tan,Juan Tao
Despite our increasing understanding of macrophage heterogeneity, drivers of macrophage phenotypic and functional polarization in the microenvironment are not fully elucidated. Here, our single-cell RNA sequencing data identify a subpopulation of macrophages expressing high levels of the phagocytic receptor MER proto-oncogene tyrosine kinase (MerTK+ macrophages), which is closely associated with melanoma progression and immunotherapy resistance. Adoptive transfer of the MerTK+ macrophages into recipient mice notably accelerated tumor growth regardless of macrophage depletion. Mechanistic studies further revealed that ALK And LTK Ligand 1 (ALKAL1), a target gene of aryl hydrocarbon receptor (AhR), facilitated MerTK phosphorylation, resulting in heightened phagocytic activity of MerTK+ macrophages and their subsequent polarization toward an immunosuppressive phenotype. Specifically targeted delivery of AhR antagonist to tumor-associated macrophages with mannosylated micelles could suppress MerTK expression and improved the therapeutic efficacy of anti–programmed cell death ligand 1 therapy. Our findings shed light on the regulatory mechanism of MerTK+ macrophages and provide strategies for improving the efficacy of melanoma immunotherapy.
研究领域:
免疫学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Matter
·
2023
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IF 18.9
Zhiqin Cao,Lanfang Ren,Le Niu,Rui Zhao,Nanhui Liu,Qi Zhuang,Feng Pan,Zhuang Liu,Yiyun Cheng,Yang Yang,Qian Chen
Summary Cancer vaccines have attracted tremendous interest in the field of cancer immunotherapy due to their ability to trigger tumor-specific immune responses to destroy cancer cells. Herein, we demonstrate that dendrimers coordinated with manganese ions (GT-Mn 2+ ) could self-assemble with peptides to form a cancer vaccine, which could be internalized by dendritic cells (DCs) via specific macropinocytosis-dependent and lipid-raft-related pathways and then dissociated gradually to release peptides to achieve efficient antigen cross-presentation and stimulate the cGAS-STING pathway. Additionally, GT-Mn 2+ could package multiple neoantigens to form an effective “personalized” cancer vaccine and has exhibited excellent therapeutic effects when used in combination with anti-PD-L1. Thus, our work presents an innovative peptide carrier to construct an effective “personalized” cancer vaccine that shows great promise to achieve effective cancer immunotherapy for different patients in clinic.
研究领域:
癌症免疫疗法
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纳米医学
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疫苗学
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产品关联
DOI
高影响因子
Advanced Healthcare Materials
·
2024
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IF 10
Yulu Teng,Zhenzhen Yang,Yiwei Peng,Yiliang Yang,Siyu Chen,Jiajia Li,Datong Gao,Wen Sun,Zinan Wu,Yanxia Zhou,Xinru Li,Xianrong Qi
Dying tumor cells regulated by immunogenic cell death (ICD) inducers are promising candidates for cancer vaccine development because of their comprehensive antigen spectrum. However, their limited immunogenicity and potential tumorigenicity hinder clinical translation. To address these challenges, a nano-orchestrator is developed that targets the endoplasmic reticulum (ER) stress, a critical pre-ICD event, to optimize the “precise dose” of ER stress. Using a clinical-range irradiation fluence (50‒200 J cm −2 ) with an 808 nm laser, the release of damage associated molecular patterns (DAMPs) and antigens are precisely regulated. A fluence of 150 J cm −2 (2 W cm −2 for 75 s) increases dendritic cell maturation and antitumor T cell proliferation, providing valuable clinical insights. The ER stress nano-orchestrator enhances both adjuvanticity and antigenicity via the protein kinase R-like endoplasmic reticulum kinase (PERK)-C/EBP homologous protein (CHOP) pathway to regulate ICD-induced DAMPs and promote tumor cell apoptosis. These optimized ER stress phototherapeutic dying tumor cells can serve as prophylactic vaccines, achieving a remarkable 100% success rate against tumor rechallenge in vivo. Additionally, the nano-orchestrator shows the potential to develop in situ therapeutic tumor vaccines when combined with anti-PD-L1 treatment, providing important insights into enhancing the efficacy of immune checkpoint regulators by modulating endogenous immune responses.
研究领域:
癌症生物学
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纳米技术
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免疫学
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治疗学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-25
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IF 16.6
Li Ting,Jiang Shuhui,Zhang Ying,Luo Jie,Li Ming,Ke Hengte,Deng Yibin,Yang Tao,Sun Xiaohui,Chen Huabing
The survival of malignant tumors is highly dependent on their intrinsic self-defense pathways such as heat shock protein (HSP) during cancer therapy. However, precisely dismantling self-defenses to amplify antitumor potency remains unexplored. Herein, we demonstrate that nanoparticle-mediated transient receptor potential vanilloid member 1 (TRPV1) channel blockade potentiates thermo-immunotherapy via suppressing heat shock factor 1 (HSF1)-mediated dual self-defense pathways. TRPV1 blockade inhibits hyperthermia-induced calcium influx and subsequent nuclear translocation of HSF1, which selectively suppresses stressfully overexpressed HSP70 for enhancing thermotherapeutic efficacy against a variety of primary, metastatic and recurrent tumor models. Particularly, the suppression of HSF1 translocation further restrains the transforming growth factor β (TGFβ) pathway to degrade the tumor stroma, which improves the infiltration of antitumor therapeutics (e.g. anti-PD-L1 antibody) and immune cells into highly fibrotic and immunosuppressive pancreatic cancers. As a result, TRPV1 blockade retrieves thermo-immunotherapy with tumor-eradicable and immune memory effects. The nanoparticle-mediated TRPV1 blockade represents as an effective approach to dismantle self-defenses for potent cancer therapy.
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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分子生物学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2022
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IF 7.033
Cunqing Kong,Banghao Xu,Guanhua Qiu,Meng Wei,Mengqi Zhang,Shengxian Bao,Jiali Tang,Lequn Li,JunJie Liu
Introduction Photoimmunotherapy is a breakthrough treatment for malignant tumors. Its uniqueness is that it uses antibody mediated targeted delivery to achieve high tumor specificity and uses laser-activated biophysical mechanism to accurately induce the rapid death of cancer cells and avoid damaging the surrounding normal tissues. Methods In this paper, an iron-based micelle was designed to encapsulate the photothermal agent indocyanine green (ICG) and a cyclic tripeptide of arginine-glycine-aspartic acid (cRGD) as targeted multifunctional ICG@SANPs-cRGD nanoparticles for combined photothermal/photodynamic/immune therapy of breast cancer. Results The experimental results show that ICG@SANPs-cRGD nanoparticles have good biocompatibility and photothermal conversion ability. Photothermal therapy (PTT) and photodynamic therapy (PDT) based on ICG@SANPs-cRGD can not only inhibit the proliferation, invasion and migration of tumor cells, but also directly kill tumor cells by inducing apoptosis or necrosis. Dual-mode fluorescence light (FL) and magnetic resonance imaging (MRI) imaging in mice confirmed the selective accumulation at tumor sites and imaging ability of ICG@SANPs-cRGD. PTT/PDT combined with Anti-PD-L1 immunotherapy based on ICG@SANPs-cRGD mediated the immunogenic cell death (ICD) of tumor cells by regulating the expression of immune-related indicators and activated the body's immune response mechanism, which enhanced the immunotherapy effect of immune checkpoint block (ICB). PTT/PDT combined with Anti-PD-L1 therapy not only prevented the progression of the primary tumor but also inhibited the distant metastasis of the tumor. Discussion This study explores the biomedical application of PTT/PDT combined with Anti-PD-L1 based on ICG@SANPs-cRGD nanomaterials for breast cancer treatment and demonstrates the potential of ICG@SANPs-cRGD as a multifunctional therapeutic platform for future cancer therapy.
研究领域:
癌症治疗
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纳米技术
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免疫学
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生物医学工程
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
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IF 13.3
Yuting Shen,Xin Guan,Shaoyue Li,Xiaodong Hou,Jifeng Yu,Haohao Yin,Xuexia Shan,Xiaoxia Han,Lifan Wang,Boyang Zhou,Xiao Li,Liping Sun,Yifeng Zhang,Huixiong Xu,Wenwen Yue
Triple-negative breast cancer (TNBC)-the most aggressive and refractory subtype of breast cancer-plagues many patients. The tumor physical microenvironment (TPME) is characterized by altered stromal composition and extracellular matrix (ECM), which may contribute to tissue stiffness and compromise therapeutic efficacy. Here, based on clinical data analysis and preclinical model validation, we discover that chemoresistant TNBC tends to have a stiffer TPME with a more aggressive genomic landscape, in which lysyl oxidase (LOX) exerts pivotal effects. Anlotinib (An), a multi-targeted tyrosine kinase inhibitor, has great promising potential in the treatment of TNBC. In this regard, we developed a tumor-softening nanobomb (An&siLOX@NPs) that remodels TPME by co-delivering small interfering siRNAs silencing LOX and the anti-angiogenic drug, anlotinib (An). The improved cytosolic delivery of siLOX enables TPME remodeling via reducing deposition and cross-linking between collagen and fibronectin, thereby promoting enrichment of An to improve its therapeutic outcomes. In chemoresistant TNBC, we confirm the An&siLOX@NPs nanobomb-mediated mechanical gene therapy results in obvious inhibition of local tumor outgrowth and prolongs survival. Additionally, softened TPME reactivates intratumoral immune milieu to bolster sensitivity to anti-PD-L1 immunotherapy, completely curing 33.3% of the metastatic tumors, further generating a synergistic anti-tumor efficacy. Collectively, our mechanical gene therapy strategy represents a highly efficient, safe, and versatile anti-drug resistance modality, which not only can solve the snag problem of TNBC treatment but also provides a new demonstration for other tumor treatments.
研究领域:
肿瘤学
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分子生物学
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基因治疗
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药理学
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产品关联
DOI
高影响因子
Science Bulletin
·
2022
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IF 20.577
Ruizhi Hu,Chen Dai,Xinyue Dai,Caihong Dong,Hui Huang,Xinran Song,Wei Feng,Li Ding,Yu Chen,Bo Zhang
Iron accumulation and lipid peroxidation form the basis of ferroptosis, potentially circumventing the limitations of apoptosis in cancer treatment. Owing to the lack of potent ferroptosis inducers, the development of efficient ferroptosis-based therapeutic agents and protocols against cancers is highly challenging. Inspired by the topological effect of nanoparticles in modulating cellular function/status, a specific tetrapod ferroptosis-inducer iron-palladium (FePd) nanocrystal was rationally engineered for physically activated autophagy-augmented ferroptosis and enhanced cancer immunotherapy. Specifically, the tetrapod FePd nanocrystal featured strong peroxidase-/glutathione oxidase-mimicking bioactivities, which promoted cancer cell ferroptosis. The special spiky morphology and nanostructure of the FePd nanocrystal simultaneously induced autophagy, which augmented ferroptosis in cancer cells and triggered the release of inflammatory cytokines in macrophages for strengthening anti-PD-L1-antibody mediated immunotherapy, synergistically achieving the maximal antineoplastic effect in three tumor-bearing animal models. This unique physical activation strategy for efficient cancer treatment via precise morphological tuning represents a paradigm for nanomedicine design for efficient tumor treatment.
研究领域:
纳米技术
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癌症研究
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免疫治疗
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2023
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IF 17.4
Anning Song,Yuwei Wang,Jialu Xu,Xiaoyu Wang,Yi Wu,Heng Wang,Chenlu Yao,Huaxing Dai,Yue Zhang,Qi Wang,Chao Wang
Photodynamic therapy (PDT) uses a combination of light and a photosensitizing agent to destroy cancerous cells. However, the PDT alone often insufficient to elicit an effective anti-tumor response due to various factors including insufficient ROS generation and the weak induced immune response. Here, we report yeast nanoparticles (YNPs) loaded with aggregation-induced emission (AIE) photosensitizer QMC12 (YNP-QMC) for enhanced photodynamic-immunotherapy in animal models . YNPs have a strong immune adjuvant effect which could significantly activate various APCs and reverse the immunosuppressive microenvironment at tumor and tumor-draining lymph nodes (TDLNs) sites. More importantly, YNP-QMC can be attached with tumor cell antigens released from dying cells after PDT. This antigen attached nanoparticle can efficiently migrate to tumor-draining lymph nodes and activate an antigen-specific systemic antitumor immunity. In combination with anti-PD-L1, this strategy could promote the elimination of primary tumors and inhibit the growth of distant tumors. Thus, our AIE photosensitizer and adjuvant YNP-powered PDT strategy provides a simple way to enhance efficacy of PDT.
研究领域:
癌症研究
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纳米技术
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免疫治疗
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光动力疗法
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）