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NIR-Ⅱ responsive Janus nanoparticles amplify immunogenic cell death for enhanced cancer immunotherapy

Science China(Technological Sciences) 2024年第1期67卷 321-329页

作者： CHEN BeiBei GUO KangLi WANG HaoRan XU Fu-Jian WANG JuLin ZHAO NaNa State Key Laboratory of Chemical Resource Engineering Beijing University of Chemical TechnologyBeijing 100029China Key Laboratory of Biomedical Materials of Natural Macromolecules(Beijing University of Chemical Technology) Beijing Laboratory of Biomedical MaterialsBeijing University of Chemical TechnologyBeijing 100029China College of Materials Sciences and Engineering Beijing University of Chemical TechnologyBeijing 100029China Beijing Key Laboratory of Electrochemical Process and Technology for Materials Beijing University of Chemical TechnologyBeijing 100029China

Immunotherapy brings new hope for tumor treatment by inducing immunogenic cell death(ICD)of tumor cells.However,insufficient immunogenicity and low immune response rate greatly limit antitumor immunity.Herein,by optimizing the composition and morphology,the rational design of Janus nanoparticles composed of Fe_(3)O_(4) nanospheres and SiO_(2)nanorods was realized for enhanced cancer immunotherapy through amplified ICD.After glucose oxidase(GOx)was loaded by the Janus nanoparticles,the resultant M-FS-GOx consumes glucose at tumor sites to generate gluconic acid and hydrogen peroxide(H_(2)O_(2))for starvation therapy while the H_(2)O_(2)supply promotes the production of highly toxic·OH to achieve effective chemodynamic therapy(CDT).Under a 1064 nm light irradiation,the photothermal effect of M-FS-GOx enhances the enzyme activity of GOx for improved starvation therapy.Furthermore,both tumor-associated antigens released during the process of ICD and the intrinsic immunoadjuvant property of M-FS-GOx stimulate dendritic cell maturation to activate antitumor immune responses.This work provides a promising strategy for the construction of Janus nanoparticles to achieve enhanced cancer immunotherapy through combination therapy-amplified ICD.

关键词： Janus nanoparticles immunogenic cell death cancer immunotherapy

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Mitochondria-targeted nano-AIEgens as a powerful inducer for evoking immunogenic cell death

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Chinese Chemical Letters 2024年第5期35卷 338-343页

作者： Kun-Heng Li Hong-Yang Zhao Dan-Dan Wang Ming-Hui Qi Zi-Jian Xu Jia-Mi Li Zhi-Li Zhang Shi-Wen Huang Key Laboratory of Biomedical Polymers of Ministry of Education Department of ChemistryWuhan UniversityWuhan 430072China

AIEgens can serve as an effective platform for the construction of photosensitizer-based immunogenic cell death(ICD)inducers.To date,several mitochondria or endoplasmic reticulum(ER)-targeted aggregationinduced emission(AIE)molecules have been developed and have evoked massive ICD in cells.However,due to the complex physicochemical environment in cells,these small AIE molecules cannot maintain a stable aggregate state,which not only affects the fluorescence intensity of the photosensitizer but also decreases the generation of reactive oxygen species(ROS),and thus reducing the effect of the photosensitizer to elicit ICD.AIEgen-based nanomicelles,which maintain a stable micellar structure,can prevent defects of AIE molecules in photodynamic therapy(PDT)applications.Therefore,in this study,a mitochondria-targeted AIE nanophotosensitizer was synthesized and used as a highly potent ICD inducer for vaccine preparation and tumor prevention.

关键词： Aggregation induced emission Photodynamic therapy immunogenic cell death Reactive oxygen species Nanophotosensitizer Mitochondria

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Investigating the immunogenic cell death‑Dependent Subtypes and Prognostic Signature of Triple‑Negative Breast Cancer

Phenomics

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Phenomics 2024年第1期4卷 34-45页

作者： Youyang Shi Yuanyuan Wu Feifei Li Kexin Jiang Xiaofang Fang Yu Wang Xiaoyun Song Rui Wang Lixin Chen Jinzhou Zheng Chunyu Wu Yuenong Qin Xiaofei Liu Sheng Liu Breast Surgery Longhua HospitalShanghai University of Traditional Chinese MedicineWanping South Road725Shanghai 200033China First Clinical College Shandong University of Traditional Chinese MedicineNo.16369Jingshi RoadLixia DistrictJinan 250011ShandongChina

Recently,immunotherapy has emerged as a promising and efective method for treating triple-negative breast cancer(TNBC).However,challenges still persist.immunogenic cell death(ICD)is considered a prospective treatment and potential combinational treatment strategy as it induces an anti-tumor immune response by presenting the antigenic epitopes of dead cells.Nevertheless,the ICD process in TNBC and its impact on disease progression and the response to immunotherapy are not well understood.In this study,we observed dysregulation of the ICD process and verifed the altered expression of prognostic ICD genes in TNBC through quantitative real-time polymerase chain reaction(qRT-PCR)analysis.To investigate the potential role of the ICD process in TNBC progression,we determined the ICD-dependent subtypes,and two were identifed.Analysis of their distinct tumor immune microenvironment(TIME)and cancer hallmark features revealed that Cluster 1 and 2 corresponded to the immune“cold”and“hot”phenotypes,respectively.In addition,we constructed the prognostic signature ICD score of TNBC patients and demonstrated its clinical independence and generalizability.The ICD score could also serve as a potential biomarker for immune checkpoint blockade and may aid in the identifcation of targeted efective agents for individualized clinical strategies.

关键词： immunogenic cell death Triple-negative breast cancer Tumor immune microenvironment Prognostic signature

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immunogenic cell death-related long noncoding RNA influences immunotherapy against lung adenocarcinoma

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Oncology Research 2023年第5期31卷 753-767页

作者： DONGJIE SUN CHI ZHANG Department of Translational Medicine The First Hospital of Jilin UniversityChangchunChina College of Basic Medical Sciences Jilin UniversityChangchunChina Department of Anesthesiology The First Hospital of Jilin UniversityChangchunChina

Lung adenocarcinoma(LUAD)is the leading cause of cancer-related deaths,accounting for over a million deaths worldwide annually.immunogenic cell death(ICD)elicits an adaptive immune response.However,the role of ICD-related long noncoding RNAs(lncRNAs)in LUAD is unknown.In this study,we investigated the characteristics of the tumor microenvironment in LUAD,the prognostic significance of ICD-related lncRNAs,and the half-maximal inhibitory concentration(IC50)of possible chemotherapeutic drugs.We sorted prognostic lncRNAs using univariate Cox regression and constructed a risk signature based on them.We then confirmed the model’s accuracy and generated a nomogram.Additionally,we performed immune microenvironment analysis,somatic mutation calculation,Tumor Immune Dysfunction and Exclusion(TIDE)analysis,and anticancer pharmaceutical IC50 prediction.Least absolute shrinkage and selection operator Cox regression identified 27 prognostic lncRNAs related to ICD,and a unique risk signature using 10 ICD-related lncRNAs was constructed.The risk score was confirmed to be a reliable predictor of survival,with the highest c-index score.The signature had a remarkable predictive performance with clinical applicability and could accurately predict the overall survival in LUAD.Furthermore,the lncRNA signature was closely associated with immunocyte invasion.We also analyzed the correlation between the risk score,tumor-infiltrating immune cells,and prognosis and identified high immune and ESTIMATE scores in low-risk patients.Moreover,we observed elevated checkpoint gene expression and low TIDE scores in high-risk patients,indicating a good immunotherapy response.Finally,high-risk patients were shown to be susceptible to anticancer medications.Therefore,our unique risk signature comprising 10 ICD-related lncRNAs was demonstrated to indicate the characteristics of the tumor-immune microenvironment in LUAD,predict patients’overall survival,and guide individualized treatment.

关键词： Lung adenocarcinoma immunogenic cell death Prognostic model Bioinformatics Tumor infiltration

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immunogenic cell death effects induced by doxorubicin improved chemo-immunotherapy via restoration of granzyme B activity

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Nano Research 2023年第12期16卷 13250-13258页

作者： Tao Huang Xiaofan Sun Yingqiu Qi Xi Yang Linyao Fan Mengdie Chen Yale Yue Hong Ge Yiye Li Guangjun Nie Huan Min Xianfu Sun Department of Breast Disease The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalHenan Institute of Advanced TechnologyZhengzhou UniversityZhengzhou 450008China Department of Pharmacology School of Basic Medical SciencesZhengzhou UniversityZhengzhou 450001China Department of Radiation Oncology The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalZhengzhou 450003China CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety&CAS Center for Excellence in Nanoscience National Center for Nanoscience and TechnologyBeijing 100190China

Chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B(GrB).However,numerous malignant cancers adaptively acquired the capacity of secreting serpinb9(Sb9),a physiological inhibitor of GrB,which can reversibly inhibit the biological activity of GrB.To circumvent this dilemma,in this study,an integrated tailor-made nanomedicine composed of tumor-targeting peptide(Arg-Gly-Asp,RGD)decorated liposome,doxorubicin(DOX,an effective ICD inducer),and the compound 3034(an inhibitor of Sb9),is developed(termed as D3RL)for breast cancer chemo-immunotherapy.In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD.Meanwhile,D3RL can competitively relieve the inhibition of Sb9 to GrB.The restored GrB can not only effectively induce tumor immunotherapy,but also degrade matrix components in the tumor microenvironment,consequently improving the infiltration of immune cells and the penetration of nanomedicines,which in return enhance the combined antitumor effect.Taken together,this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.

关键词： immunogenic cell death granzyme B serpinb9 chemo-immunotherapy nanomedicine

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Stimuli-responsive nano vehicle enhances cancer immunotherapy by coordinating mitochondria-targeted immunogenic cell death and PD-L1 blockade

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2533-2549页

作者： Qiuyi Li Cheng Chen Jinxia Kong Lian Li Junlin Li Yuan Huang Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin(DOX) massively amplified ICD via substantial generation of reactive oxygen species(ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways:(1) ROS elevated endoplasmic reticulum(ER) stress, leading to surface exposure of calreticulin;(2) ROS promoted release of various mitochondriaassociated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback,we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.

关键词： immunogenic cell death Mitochondrial targeting PD-L1 blockade Endoplasmic reticulum stress Mitochondria-associated damage molecules Stimuli-responsive Antitumor immune responses Antitumor efficacy

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Perfluorooctyl bromide nanoemulsions holding MnO_(2) nanoparticles with dual-modality imaging and glutathione depletion enhanced HIFU-eliciting tumor immunogenic cell death

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Acta Pharmaceutica Sinica B 2022年第2期12卷 967-981页

作者： Xinping Kuai Yuefei Zhu Zheng Yuan Shengyu Wang Lin Lin Xiaodan Ye Yiping Lu Yu Luo Zhiqing Pang Daoying Geng Bo Yin Department of Radiology Huashan HospitalFudan UniversityShanghai 200040China School of Pharmacy Fudan UniversityKey Laboratory of Smart Drug DeliveryMinistry of EducationShanghai 201203China Department of Radiology Shanghai First Maternity and Infant HospitalTongji University School of MedicineShanghai 201204China Department of Radiology Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai 201800China Department of Radiology Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghai 200030China State Key Laboratory of High Performance Ceramics and Superfine Microstructure School of Chemical Science and EngineeringShanghai 200092China

Tumor-targeted immunotherapy is a remarkable breakthrough,offering the inimitable advantage of specific tumoricidal effects with reduced immune-associated cytotoxicity.However,existing platforms suffer from low efficacy,inability to induce strong immunogenic cell death(ICD),and restrained capacity of transforming immune-deserted tumors into immune-cultivated ones.Here,an innovative platform,perfluorooctyl bromide(PFOB)nanoemulsions holding MnO_(2) nanoparticles(MBP),was developed to orchestrate cancer immunotherapy,serving as a theranostic nanoagent for MRI/CT dual-modality imaging and advanced ICD.By simultaneously depleting the GSH and eliciting the ICD effect via highintensity focused ultrasound(HIFU)therapy,the MBP nanomedicine can regulate the tumor immune microenvironment by inducing maturation of dendritic cells(DCs)and facilitating the activation of CD8^(+)and CD4^(+)T cells.The synergistic GSH depletion and HIFU ablation also amplify the inhibition of tumor growth and lung metastasis.Together,these findings inaugurate a new strategy of tumor-targeted immunotherapy,realizing a novel therapeutics paradigm with great clinical significance.

关键词： immunogenic cell death Nanoemulsions Manganese dioxide nanoparticles Glutathione depletion Dual-modality imaging High-intensity focused ultrasound Tumor microenvironment

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Enzyme-instructed and mitochondria-targeting peptide self-assembly to efficiently induce immunogenic cell death

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2740-2750页

作者： Debin Zheng Jingfei Liu Limin Xie Yuhan Wang Yinghao Ding Rong Peng Min Cui Ling Wang Yongjie Zhang Chunqiu Zhang Zhimou Yang Key Laboratory of Bioactive Materials Ministry of EducationState Key Laboratory of Medicinal Chemical BiologyCollege of Life SciencesCollaborative Innovation Center of Chemical Science and EngineeringNational Institute of Functional MaterialsNankai UniversityTianjin 300071China College of Pharmacy Nankai UniversityTianjin 300071China Department of Human Anatomy Nanjing Medical UniversityNanjing 211166China

immunogenic cell death(ICD) plays a major role in cancer immunotherapy by stimulating specific T cell responses and restoring the antitumor immune system.However,effective type Ⅱ ICD inducers without biotoxicity are still very limited.Herein,a tentative drug-or photo sensitizer-free strategy was developed by employing enzymatic self-assembly of the peptide F-pY-T to induce mitochondrial oxidative stress in cancer cells.Upon dephosphorylation catalyzed by alkaline phosphatase overexpressed on cancer cells,the peptide F-pY-T self-assembled to form nanoparticles,which were subsequently internalized.These affected the morphology of mitochondria and induced serious reactive oxygen species production,causing the ICD characterized by the release of danger-associated molecular patterns(DAMPs).DAMPs enhanced specific immune responses by promoting the maturation of DCs and the intratumoral infiltration of tumor-specific T cells to eradicate tumor cells.The dramatic immunotherapeutic capacity could be enhanced further by combination therapy of F-pY-T and anti-PD-L1 agents without visible biotoxicity in the main organs.Thus,our results revealed an alternative strategy to induce efficient ICD by physically promoting mitochondrial oxidative stress.

关键词： immunogenic cell death Self-assembly Mitochondria targeting Enzyme

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Evoking robust immunogenic cell death by synergistic sonodynamic therapy and glucose depletion using Au clusters/single atoms modified TiO_(2)nanosheets

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Nano Research 2023年第7期16卷 9730-9742页

作者： Xiuxin Lu Kun Qiao Firdoz Shaik Yang Zheng Zhaoyou Chu Haisheng Qian Xijun Liu Weiqing Zhang Department of Research Guangxi Medical University Cancer HospitalNanning 530021China Department of Breast Surgery Harbin Medical University Cancer HospitalHarbin 150081China Department of Biotechnology Vignan’s Foundation for ScienceTechnology&ResearchGuntur 522213India Department of Breast Surgery Guangxi Medical University Cancer HospitalNanning 530021China School of Biomedical Engineering Research and Engineering Center of Biomedical MaterialsAnhui Provincial Institute of Translational MedicineAnhui Medical UniversityHefei 230032China State Key Laboratory of Featured Metal Materials and Life-cycle Safety for Composite Structures School of ResourceEnvironments and MaterialsGuangxi UniversityNanning 530004China

Facilitated by reactive oxygen species(ROS)-involved therapies,tumor cells undergo immunogenic cell death(ICD)to stimulate long-term immunity response.However,it is hard to trigger abundant and large-scale ICD for satisfactory cancer immunotherapy.Herein,a multifunctional sonosensitizer that consists of Au single atoms and clusters anchored on TiO_(2)nanosheets(named Au_(S/C)-TiO_(2))is reported for augmented sonodynamic therapy(SDT)and glucose depletion,which ultimately induce robust ICD due to the improved ROS generation and strong endoplasmic reticulum(ER)stress.The synergy effect between Au cluster/single atom with TiO_(2)nanosheets intensifies apoptosis and ICD pathways to inhibit 80%of tumor cells through in vivo analyses.Furthermore,immune cells in vivo analyses verify the effectiveness of Au_(S/C)-TiO_(2)sonosensitizer towards the induction of antitumor immunity.This study thus reveals that simultaneous presence of ROS generation and strong ER stress can efficiently evoke a strong ICD-mediated immune response.

关键词： single atom cluster titania sonodynamic therapy immunogenic cell death multifunctional

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Activation of pyroptosis by specific organelle-targeting photodynamic therapy to amplify immunogenic cell death for anti-tumor immunotherapy

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Bioactive Materials 2023年第7期25卷 580-593页

作者： Shuang Zeng Chen Chen Liuwei Zhang Xiaosheng Liu Ming Qian Hongyan Cui Jingyun Wang Qixian Chen Xiaojun Peng School of Bioengineering Dalian University of Technology2 Linggong RoadHi-tech ZoneDalian116024China State Key Laboratory of Fine Chemicals Dalian University of Technology2 Linggong RoadHi-tech ZoneDalian116024China

Pyroptosis,a unique lytic programmed cell death,inspired tempting implications as potent anti-tumor strategy in pertinent to its potentials in stimulating anti-tumor immunity for eradication of primary tumors and metastasis.Nonetheless,rare therapeutics have been reported to successfully stimulate pyroptosis.In view of the intimate participation of reactive oxygen species(ROS)in stimulating pyroptosis,we attempted to devise a spectrum of well-defined subcellular organelle(including mitochondria,lysosomes and endoplasmic reticulum)-targeting photosensitizers with the aim of precisely localizing ROS(produced from photosensitizers)at the subcellular compartments and explore their potentials in urging pyroptosis and immunogenic cell death(ICD).The subsequent investigations revealed varied degrees of pyroptosis upon photodynamic therapy(PDT)towards cancerous cells,as supported by not only observation of the distinctive morphological and mechanistic characteristics of pyroptosis,but for the first-time explicit validation from comprehensive RNA-Seq analysis.Furthermore,in vivo anti-tumor PDT could exert eradication of the primary tumors,more importantly suppressed the distant tumor and metastatic tumor growth through an abscopal effect,approving the acquirement of specific anti-tumor immunity as a consequence of pyroptosis.Hence,pyroptosis was concluded unprecedently by our proposed organelles-targeting PDT strategy and explicitly delineated with molecular insights into its occurrence and the consequent ICD.

关键词： Pyroptosis Tumor Photodynamic therapy immunogenic cell death Subcellular targeting

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