Jingyi An , Rong Guo , Mengyuan Liu , Haiying Hu , Hongling Zhang
{"title":"通过逆转 T 细胞衰竭增强化疗免疫疗法的多模式 Ca2+ 纳米发电机","authors":"Jingyi An , Rong Guo , Mengyuan Liu , Haiying Hu , Hongling Zhang","doi":"10.1016/j.jconrel.2024.06.066","DOIUrl":null,"url":null,"abstract":"<div><p>Chemo-immunotherapy holds the advantage of specific antitumor effects by activating cytotoxic lymphocyte cells (CTLs) immune response. However, multiple barriers have limited the outcomes partly due to tumor-cell-mediated exhaustion of CTLs in the immunosuppressive tumor microenvironment (iTME). Here, we rationally designed a simple-yet-versatile Ca<sup>2+</sup> nanogenerator to modulate iTME for enhancing 2-deoxyglucose (2-DG) mediated chemo-immunotherapy. Briefly, after 2-DG chemotherapy, CaO<sub>2</sub> nanoparticles coated with EL4 cell membrane (denoted as CaNP@ECM) could preferentially accumulate in tumor tissue <em>via</em> adhesion between LFA-1 on EL4 cell membrane and ICAM-1 on inflamed endothelial cell in tumor tissues and display a series of benefits for CTLs: i) Increasing glucose availability of CTLs while reducing lactic acid secretion through Ca<sup>2+</sup> overloading mediated inhibition of tumor cell glycolysis, as well as relieving hypoxia; ii) Reversing CTLs exhaustion <em>via</em> TGF-β1 scavenging and PD-L1 blockade through PD-1 and TGF-β1R on EL4 cell membrane; iii) Boosting tumor immunotherapy <em>via</em> immunologic death (ICD) of tumor cells induced by Ca<sup>2+</sup> overloading. We demonstrate that the multi-modal Ca<sup>2+</sup> nanogenerator rescues T cells from exhaustion and inhibits tumor growth both <em>in vitro</em> and <em>in vivo</em>. More importantly, the study also facilitate the development of glucose metabolism inhibition-based tumor immunotherapy <em>via</em> Ca<sup>2+</sup> overloading.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5000,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Multi-modal Ca2+ nanogenerator via reversing T cell exhaustion for enhanced chemo-immunotherapy\",\"authors\":\"Jingyi An , Rong Guo , Mengyuan Liu , Haiying Hu , Hongling Zhang\",\"doi\":\"10.1016/j.jconrel.2024.06.066\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Chemo-immunotherapy holds the advantage of specific antitumor effects by activating cytotoxic lymphocyte cells (CTLs) immune response. However, multiple barriers have limited the outcomes partly due to tumor-cell-mediated exhaustion of CTLs in the immunosuppressive tumor microenvironment (iTME). Here, we rationally designed a simple-yet-versatile Ca<sup>2+</sup> nanogenerator to modulate iTME for enhancing 2-deoxyglucose (2-DG) mediated chemo-immunotherapy. Briefly, after 2-DG chemotherapy, CaO<sub>2</sub> nanoparticles coated with EL4 cell membrane (denoted as CaNP@ECM) could preferentially accumulate in tumor tissue <em>via</em> adhesion between LFA-1 on EL4 cell membrane and ICAM-1 on inflamed endothelial cell in tumor tissues and display a series of benefits for CTLs: i) Increasing glucose availability of CTLs while reducing lactic acid secretion through Ca<sup>2+</sup> overloading mediated inhibition of tumor cell glycolysis, as well as relieving hypoxia; ii) Reversing CTLs exhaustion <em>via</em> TGF-β1 scavenging and PD-L1 blockade through PD-1 and TGF-β1R on EL4 cell membrane; iii) Boosting tumor immunotherapy <em>via</em> immunologic death (ICD) of tumor cells induced by Ca<sup>2+</sup> overloading. We demonstrate that the multi-modal Ca<sup>2+</sup> nanogenerator rescues T cells from exhaustion and inhibits tumor growth both <em>in vitro</em> and <em>in vivo</em>. More importantly, the study also facilitate the development of glucose metabolism inhibition-based tumor immunotherapy <em>via</em> Ca<sup>2+</sup> overloading.</p></div>\",\"PeriodicalId\":15450,\"journal\":{\"name\":\"Journal of Controlled Release\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":10.5000,\"publicationDate\":\"2024-07-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Controlled Release\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0168365924004267\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Controlled Release","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0168365924004267","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Multi-modal Ca2+ nanogenerator via reversing T cell exhaustion for enhanced chemo-immunotherapy
Chemo-immunotherapy holds the advantage of specific antitumor effects by activating cytotoxic lymphocyte cells (CTLs) immune response. However, multiple barriers have limited the outcomes partly due to tumor-cell-mediated exhaustion of CTLs in the immunosuppressive tumor microenvironment (iTME). Here, we rationally designed a simple-yet-versatile Ca2+ nanogenerator to modulate iTME for enhancing 2-deoxyglucose (2-DG) mediated chemo-immunotherapy. Briefly, after 2-DG chemotherapy, CaO2 nanoparticles coated with EL4 cell membrane (denoted as CaNP@ECM) could preferentially accumulate in tumor tissue via adhesion between LFA-1 on EL4 cell membrane and ICAM-1 on inflamed endothelial cell in tumor tissues and display a series of benefits for CTLs: i) Increasing glucose availability of CTLs while reducing lactic acid secretion through Ca2+ overloading mediated inhibition of tumor cell glycolysis, as well as relieving hypoxia; ii) Reversing CTLs exhaustion via TGF-β1 scavenging and PD-L1 blockade through PD-1 and TGF-β1R on EL4 cell membrane; iii) Boosting tumor immunotherapy via immunologic death (ICD) of tumor cells induced by Ca2+ overloading. We demonstrate that the multi-modal Ca2+ nanogenerator rescues T cells from exhaustion and inhibits tumor growth both in vitro and in vivo. More importantly, the study also facilitate the development of glucose metabolism inhibition-based tumor immunotherapy via Ca2+ overloading.
期刊介绍:
The Journal of Controlled Release (JCR) proudly serves as the Official Journal of the Controlled Release Society and the Japan Society of Drug Delivery System.
Dedicated to the broad field of delivery science and technology, JCR publishes high-quality research articles covering drug delivery systems and all facets of formulations. This includes the physicochemical and biological properties of drugs, design and characterization of dosage forms, release mechanisms, in vivo testing, and formulation research and development across pharmaceutical, diagnostic, agricultural, environmental, cosmetic, and food industries.
Priority is given to manuscripts that contribute to the fundamental understanding of principles or demonstrate the advantages of novel technologies in terms of safety and efficacy over current clinical standards. JCR strives to be a leading platform for advancements in delivery science and technology.