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Acta Pharmaceutica Sinica B 2023年第5期13卷 2176-2187页

作者： Chuan Hu Yujun Song Yiwei Zhang Siqin He Xueying Liu Xiaotong Yang Tao Gong Yuan Huang Huile Gao Key Laboratory of Drug Targeting and Drug Delivery Systems West China School of PharmacySichuan UniversityChengdu 610041China

Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination ***,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is developed by conjugating polypeptide inhibitor of PD-1 signal pathway(AUNP-12),which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2(MMP-2)cleavable peptide(GPLGVRGD).This targeted liposome is prepared through a mature preparation process,and indoleamine-2,3-dioxygenase(IDO)inhibitor NLG919 was encapsulated into ***,mediated by the enhanced permeability and retention effect(EPR effect)and AUNP-12,NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor *** the same time,the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12,thus realizing the precise block of PD-1 signal pathway,and restoring the activity of T *** exposure of secondary targeting moduleⅡVRGDC-NLG919@Lip mediated tumor cells targeting,and further relieved the immunosuppressive ***,this study offers a potentially appealing paradigm of a high efficiency,low toxicity,and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer,which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.

关键词： Immunotherapy Cascade targeting Liposome MMP-2 responsive Breast cancer ICBs IDO inhibitors immunosuppressive microenvironment

BRAF_(V600E)mutant colorectal cancer cells mediate local immunosuppressive microenvironment through exosomal long noncoding RNAs

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World Journal of Gastrointestinal Oncology 2021年第12期13卷 2129-2148页

作者： Jie Zhi Xiao-Jing Jia Jing Yan Hui-Cong Wang Bo Feng Han-Ying Xing Yi-Tao Jia Department of Oncology Hebei General HospitalShijiazhuang 050051Hebei ProvinceChina Department of Oncology The First Hospital of ShijiazhuangShijiazhuang 050051Hebei ProvinceChina Department of Oncology Puyang People’s HospitalPuyang 457000Henan ProvinceChina Clinical Medical Research Center Hebei General HospitalShijiazhuang 050051Hebei ProvinceChina

BACKGROUND BRAF^(V600E) mutated colorectal cancer(CRC)is prone to peritoneal and distant lymph node metastasis and this correlates with a poor *** BRAF^(V600E) mutation is closely related to the formation of an immunosuppressive ***,the correlation between BRAF^(V600E) mutation and changes in local immune microenvironment of CRC is not *** To explore the effect and mechanism of BRAF^(V600E) mutant on the immune microenvironment of *** Thirty patients with CRC were included in this study:20 in a control group and 10 in a treatment *** density of microvessels and microlymphatic vessels,and M2 subtype macrophages in tumor tissues were detected by *** and functional analysis of exosomal long noncoding RNAs(lncRNAs)were performed by *** proliferation and migration of human umbilical vein endothelial cells(HUVECs)and human lymphatic endothelial cells(HLECs)were detected by CCK-8 assay and scratch test,*** tube-forming ability of endothelial cells was detected by tube formation *** macrophage subtypes were obtained by flow *** expression of vascular endothelial growth factor(VEGF)-A,basic fibroblast growth factor(bFGF),transforming growth factor(TGF)-β1,VEGF-C,claudin-5,occludin,zonula occludens(ZO)-1,fibroblast activation protein,andα-smooth muscle actin was assessed by western blot *** levels of cytokines interleukin(IL)-6,TGF-β1,and VEGF were assessed by enzyme-linked immunosorbent *** BRAF^(V600E) mutation was positively correlated with the increase of preoperative serum carbohydrate antigen 19-9(P<0.05),and with poor tumor tissue differentiation in CRC(P<0.01).Microvascular density and microlymphatic vessel density in BRAF^(V600E) mutant CRC tissues were higher than those in BRAF wildtype CRC(P<0.05).The number of CD163+M2 macrophages in BRAF^(V600E) mutant CRC tumor tissue was markedly increased(P<0.05).Compared with exosomes f

关键词： Colorectal cancer BRAF^(V600E)mutant Exosome Long noncoding RNA immunosuppressive microenvironment

Glioblastoma cells promote M2 TAMs-induced immunosuppressive microenvironment leading to malignant development of glioblastoma through activation of ALOX5/5-HETE metabolic pathway

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Glioblastoma cells promote M2 TAMs-induced immunosuppressive...

Dual-responsive supramolecular photodynamic nanomedicine with activatable immunomodulation for enhanced antitumor therapy

第十五届中国医师协会神经外科医师年会

作者： Zhuohao Liu Xinzhi Yang Jiangang Liu Hongchao Xu Dinglan Wu Jie Mao Department of Neurosurgery Shenzhen HospitalSouthern Medical University Shenzhen Key Laboratory of Viral Oncology The Clinical Innovation & Research CentreShenzhen HospitalSouthern Medical University

Background:immunosuppressive microenvironment is pivotal for the malignant development of glioblastoma,but the underlying molecular mechanism that GBM cells promote immunosuppressive microenvironment remains *** preliminary data revealed that 5-HETE is significantly upregulated in cerebrospinal fluid of GBM patient,and its key enzyme ALOX5 is also positively correlated with GBM *** we aim to explore the role of ALOX5/5-HETE in the regulation of GBM immunosuppressive ***:ALOX5 overexpressing GBM cell line and GBM orthotopic mouse model were *** molecular mechanism by which ALOX5/5-HETE regulates GBM immunosuppressive microenvironment was elucidated using both in vivo and in vitro ***:A remarkable up-regulation of 5-HETE was observed in cerebrospinal fluid of GBM *** key enzyme ALOX5 was increased in GBM and positively correlated with GBM *** of ALOX5 in GBM cells promoted orthotopic tumor progression and shortened *** vitro studies showed that proliferation,cell survival and migration capacity of ALOX5 overexpressing GBM cells were not ***,immune cell profiling revealed that overexpression of ALOX5 in GBM cells accelerated M2 tumor associated macrophages（TAMs） accumulation in ***,both conditional medium harvested from GBM cells with ALOX5 overexpression and medium supplemented with 5-HETE promoted M2 polarization in THP-1 monocyte cell ***:ALOX5/5-HETE metabolic pathway of GBM cells was activated during GBM *** cells secreted 5-HETE into the tumor microenvironment,promoting TAMs infiltration and M2 polarization in a paracrine-dependent *** M2 TAMs triggered immunosuppressive microenvironment leading to malignant development of GBM.

关键词： Glioblastoma ALOX5 5-HETE M2 TAMs immunosuppressive microenvironment

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Acta Pharmaceutica Sinica B 2024年第2期14卷 765-780页

作者： Siqin He Lulu Wang Dongxu Wu Fan Tong Huan Zhao Hanmei Li Tao Gong Huile Gao Yang Zhou Key Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical SciencesHainan UniversityHaikou 570200China Key Laboratory of Drug-Targeting and Drug Delivery System West China School of PharmacySichuan UniversityChengdu 610041China Revvity Inc. WalthamMA 02451USA School of Food and Biological Engineering Chengdu UniversityChengdu 610106China

A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment(TME), a supramolecular photodynamic nanoparticle(DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin(DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration(Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of *** guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

关键词： Photodynamic therapy immunosuppressive microenvironment Immunomodulator Dual-responsive Supramolecularassembly Checkpointblockade

Blockading a new NSCLC immunosuppressive target by pluripotent autologous tumor vaccines magnifies sequential immunotherapy

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Bioactive Materials 2022年第7期7卷 223-238页

作者： Hong Wu Hongyan Li Yiqiang Liu Jingchen Liang Qianshi Liu Zhigang Xu Zhongzhu Chen Xia Zhang Kun Zhang Chuan Xu Integrative Cancer Center&Cancer Clinical Research Center Sichuan Cancer Hospital&InstituteSichuan Cancer Center School of MedicineUniversity of Electronic Science and Technology of ChinaNo.55Section 4South Ren-min RoadChengdu610042SichuanPR China Department of Medical Ultrasound and Central Laboratory Shanghai Tenth People’s HospitalUltrasound Research and Education InstituteTongji University School of MedicineNo.301 Yan-chang-zhong RoadShanghai200072PR China International Academy of Targeted Therapeutics and Innovation Chongqing University of Arts and SciencesNO.319Red River AvenueYong-chuan402160ChongqingPR China Institute of Pathology and Southwest Cancer Center Southwest HospitalThird Military Medical University(Army Medical University)NO.30Gao-tan-yan-zheng StreetChongqing400038PR China

The presence of multiple immunosuppressive targets and insufficient activation and infiltration of cytotoxic T lymphocytes(CTLs)allow tumor cells to escape immune surveillance and disable anti-PD-1/PD-L1 ***-engineered autologous tumor vaccines(ATVs)that were camouflaged by tumor cell membrane(TCM)were designed to activate and facilitate CTLs infiltration for killing the unprotected lung tumor cells,consequently realizing the sequential ***5 was firstly screened out as a new immunosuppressive target of lung cancer in clinical *** afterwards,phosphodiesterase-5(PDE5)and programmed cell death 1 ligand 1(PD-L1)dual-target co-inhibition was proposed to unfreeze the immunosuppressive microenvironment of *** studies validated that this ATVs-unlocked sequential immunotherapy after co-encapsulating PDE5 inhibitor and NO donor(i.e.,L-arginine)exerted robust anti-tumor effects through increasing inducible nitric oxide synthase(iNOS)expression,blockading PDE5 pathway and activating systematic immune responses,which synergistically eradicated local and abscopal lung cancers in either orthotopic or subcutaneous *** pluripotent ATVs that enable PDE5 inhibition and sequential immunotherapy provide a new avenue to mitigate immunosuppressive microenvironment and magnify anti-PD-1/PD-L1 immunotherapy.

关键词： Autologous tumor vaccines(ATVs) Sequential immunotherapy immunosuppressive microenvironment Tumor tropism Immune escape target

Reverse immune suppressive microenvironment in tumor draining lymph nodes to enhance anti-PD1 immunotherapy via nanovaccine complexed microneedle

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Nano Research 2020年第6期13卷 1509-1518页

作者： Zhongzheng Zhou Jianhui Pang Xuanjin Wu Wei Wu Xiguang Chen Ming Kong College of Marine Life Science Ocean University of China5 Yushan RoadQingdao266003China Qingdao National Laboratory for Marine Science and Technology Wenhai RoadQingdao266237China

The maturation of dendritic cells(DCs)and infiltration effector T cells in tumor-draining lymph node(tdLN)and tumor tissue are crucial for *** constructive progresses have been made with anti-programmed death-1(anti-PD1)checkpoint blockade for immunotherapy,the efficacy of PD1/PD-L1 therapy deserves to be ***,we constructed a novel transfersomes based nanovaccine complexed microneedles to enhance anti-PD1 immunotherapy via transdermal immunization for skin tumor *** were functionalized with DCs targeting moietyαCD40,co-encapsulated with antigens and adjuvant poly I:***,transdermal administration promoted accumulation in tumor-draining lymph nodes(tdLN),which could facilitate cellular uptake,activate DCs maturation and enhance Th1 immune *** a mouse melanoma model,combined therapy of such nanovaccine complexed microneedles with pembrolizumab(αPD1)was able to enhance cytotoxic T lymphocytes activation,promote infiltration and reduce regulatory T cells frequency in tdLN and tumor tissues,which achieved reversion of the immunosuppressive microenvironment into immune *** study highlighted the potential of transfersomes based nanovaccines complexed microneedles as an attractive platform for tumor immunotherapy.

关键词： transfersomes microneedles immunosuppressive microenvironment tumor draining lymph node αPD1

Smart drug delivery systems to overcome drug resistance in cancer immunotherapy

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Cancer Biology & Medicine 2023年第4期20卷 248-267页

作者： Wenzhe Yi Dan Yan Dangge Wang Yaping Li State Key Laboratory of Drug Research&Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Department of Pharmaceutics School of PharmacyNanjing Medical UniversityNanjing 211116China Yantai Key Laboratory of Nanomedicine&Advanced Preparations Yantai Institute of Materia MedicaYantai 264000China Shandong Laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantai 264000China

Cancer immunotherapy,a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity,is currently an important clinical strategy for cancer treatment;however,tumors can develop drug resistance to immune surveillance,resulting in poor response rates and low therapeutic *** addition,changes in genes and signaling pathways in tumor cells prevent susceptibility to immunotherapeutic ***,tumors create an immunosuppressive microenvironment via immunosuppressive cells and secrete molecules that hinder immune cell and immune modulator infiltration or induce immune cell *** address these challenges,smart drug delivery systems(SDDSs)have been developed to overcome tumor cell resistance to immunomodulators,restore or boost immune cell activity,and magnify immune *** combat resistance to small molecules and monoclonal antibodies,SDDSs are used to co-deliver numerous therapeutic agents to tumor cells or immunosuppressive cells,thus increasing the drug concentration at the target site and improving ***,we discuss how SDDSs overcome drug resistance during cancer immunotherapy,with a focus on recent SDDS advances in thwarting drug resistance in immunotherapy by combining immunogenic cell death with immunotherapy and reversing the tumor immunosuppressive *** that modulate the interferon signaling pathway and improve the efficacy of cell therapies are also ***,we discuss potential future SDDS perspectives in overcoming drug resistance in cancer *** believe that this review will contribute to the rational design of SDDSs and development of novel techniques to overcome immunotherapy resistance.

关键词： Cancer immunotherapy drug resistance smart drug delivery system immunosuppressive microenvironment immune cell

Emerging role of natural products in cancer immunotherapy

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1163-1185页

作者： Songtao Dong Xiangnan Guo Fei Han Zhonggui He Yongjun Wang Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China School of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China

Cancer immunotherapy has become a new generation of anti-tumor treatment,but its indications still focus on several types of tumors that are sensitive to the immune ***,effective strategies that can expand its indications and enhance its efficiency become the key element for the further development of cancer *** products are reported to have this effect on cancer immunotherapy,including cancer vaccines,immune-check points inhibitors,and adoptive immune-cells *** the mechanism of that is mainly attributed to the remodeling of the tumorimmunosuppressive microenvironment,which is the key factor that assists tumor to avoid the recognition and attack from immune system and cancer ***,this review summarizes and concludes the natural products that reportedly improve cancer immunotherapy and investigates the *** we found that saponins,polysaccharides,and flavonoids are mainly three categories of natural products,which reflected significant effects combined with cancer immunotherapy through reversing the tumor-immunosuppressive ***,this review also collected the studies about nano-technology used to improve the disadvantages of natural *** of these studies showed the great potential of natural products in cancer immunotherapy.

关键词： Natural products Cancer immunotherapy immunosuppressive microenvironment Cancer vaccines Immuno-check points Adoptive immune-cells transfer immunotherapy

Anti-PD-L1 antibody enhances curative effect of cryoablation via antibody-dependent cell-mediated cytotoxicity mediating PD-L1^(high)CD11b^(+)cells elimination in hepatocellular carcinoma

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Acta Pharmaceutica Sinica B 2023年第2期13卷 632-647页

作者： Jizhou Tan Ting Liu Wenzhe Fan Jialiang Wei Bowen Zhu Yafang Liu Lingwei Liu Xiaokai Zhang Songling Chen Haibiao Lin Yuanqing Zhang Jiaping Li Department of Interventional Oncology the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Department of Stomatology the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Department of Laboratory Medicine the Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of TraditionalChinese MedicineGuangzhou 510120China Second Clinical Medical College Guangzhou University of Chinese MedicineGuangzhou 510006China School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China

Cryoablation(CRA)and microwave ablation(MWA)are two main local treatments for hepatocellular carcinoma(HCC).However,which one is more curative and suitable for combining with immunotherapy is still ***,CRA induced higher tumoral PD-L1 expression and more T cells infiltration,but less PD-L1^(high)CD11b^(+)myeloid cells infiltration than MWA in ***,CRA had better curative effect than MWA for anti-PD-L1 combination therapy in mouse ***,anti-PD-L1 antibody facilitated infiltration of CD8^(+)T cells by enhancing the secretion of CXCL9 from cDC1 cells after CRA *** the other hand,anti-PD-L1 antibody promoted the infiltration of NK cells to eliminate PD-L1^(high)CD11b^(+)myeloid cells by antibody-dependent cell-mediated cytotoxicity(ADCC)effect after CRA *** aspects relieved the immunosuppressive microenvironment after CRA ***,the wild-type PD-L1 Avelumab(Bavencio),compared to the mutant PD-L1 atezolizumab(Tecentriq),was better at inducing the ADCC effect to target PD-L1^(high)CD11b^(+)myeloid ***,our study uncovered the novel insights that CRA showed superior curative effect than MWA in combining with anti-PD-L1 antibody by strengthening CTL/NK cell immune responses,which provided a strong rationale for combining CRA and PD-L1 blockade in the clinical treatment for HCC.

关键词： Hepatocellular carcinoma Immunotherapy Cryoablation Microwave ablation CXCL9 NK cells Antibody-dependent cell-mediated cytotoxicity immunosuppressive microenvironment

Identification and Validation of an Immune-Related lncRNA Signature to Facilitate Survival Prediction in Gastric Cancer

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Identification and Validation of an Immune-Related lncRNA Si...