Xue Shi , Xiejun Zhao , Yinli He , Linpei Zhang , Xinmin Zheng , Xiangchuan Qin , Kefeng Li , Jing Li , Yawen Wang , Liangliang Dai , Xiaojiao Li
{"title":"在PD-L1抗体治疗耐药的肿瘤中,翻译后重塑胶束逆转细胞表面和外泌体PD-L1免疫抑制","authors":"Xue Shi , Xiejun Zhao , Yinli He , Linpei Zhang , Xinmin Zheng , Xiangchuan Qin , Kefeng Li , Jing Li , Yawen Wang , Liangliang Dai , Xiaojiao Li","doi":"10.1016/j.jconrel.2025.113961","DOIUrl":null,"url":null,"abstract":"<div><div>Sustained replenishment of cell-surface and exosomal PD-L1 has been believed as the most important factor in the progression of PD-L1 antibody therapy resistance. Given that direct genetic blockade of PD-L1 may lead to unintended consequences and that posttranslational modifications (PTMs) are often used as pharmacological targets of cancer therapy, approaches targeting PD-L1 PTMs show great potential as new therapeutic paradigms. Palmitoylation has emerged as a critical PTM for modulating PD-L1 stability and distribution. In this work, it is found that disruption of palmitoylation by 2-bromopalmitate (2-BP) dual-impaired PD-L1 on the cell surface and exosomes. An amphiphilic TME-responsive micelle was fabricated to efficiently deliver 2-BP and the chemotherapeutic agent cisplatin to tumor milieu. The composite formulation unifying elimination of cell-surface and exosomal PD-L1 with chemotherapy synergistically relieved immunosuppression in the tumor bed and draining lymph node, thereby dramatically restraining growth, postsurgical relapse, and metastasis in melanoma resistant to PD-L1 antibody therapy. Moreover, the formulation elicits potent T cell memory responses for long-term protection against tumor rechallenge. In summary, our study takes advantage of an amphiphilic nanoformula combination of a posttranslational modifier and chemotherapy to target tumors resistant to PD-L1 antibody therapy, and paves a new path for multimodal cancer treatment.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"384 ","pages":"Article 113961"},"PeriodicalIF":10.5000,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Posttranslational remodeling micelle reverses cell-surface and exosomal PD-L1 immunosuppression in tumors resistant to PD-L1 antibody therapy\",\"authors\":\"Xue Shi , Xiejun Zhao , Yinli He , Linpei Zhang , Xinmin Zheng , Xiangchuan Qin , Kefeng Li , Jing Li , Yawen Wang , Liangliang Dai , Xiaojiao Li\",\"doi\":\"10.1016/j.jconrel.2025.113961\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Sustained replenishment of cell-surface and exosomal PD-L1 has been believed as the most important factor in the progression of PD-L1 antibody therapy resistance. Given that direct genetic blockade of PD-L1 may lead to unintended consequences and that posttranslational modifications (PTMs) are often used as pharmacological targets of cancer therapy, approaches targeting PD-L1 PTMs show great potential as new therapeutic paradigms. Palmitoylation has emerged as a critical PTM for modulating PD-L1 stability and distribution. In this work, it is found that disruption of palmitoylation by 2-bromopalmitate (2-BP) dual-impaired PD-L1 on the cell surface and exosomes. An amphiphilic TME-responsive micelle was fabricated to efficiently deliver 2-BP and the chemotherapeutic agent cisplatin to tumor milieu. The composite formulation unifying elimination of cell-surface and exosomal PD-L1 with chemotherapy synergistically relieved immunosuppression in the tumor bed and draining lymph node, thereby dramatically restraining growth, postsurgical relapse, and metastasis in melanoma resistant to PD-L1 antibody therapy. Moreover, the formulation elicits potent T cell memory responses for long-term protection against tumor rechallenge. In summary, our study takes advantage of an amphiphilic nanoformula combination of a posttranslational modifier and chemotherapy to target tumors resistant to PD-L1 antibody therapy, and paves a new path for multimodal cancer treatment.</div></div>\",\"PeriodicalId\":15450,\"journal\":{\"name\":\"Journal of Controlled Release\",\"volume\":\"384 \",\"pages\":\"Article 113961\"},\"PeriodicalIF\":10.5000,\"publicationDate\":\"2025-06-14\",\"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/S0168365925005814\",\"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/S0168365925005814","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Posttranslational remodeling micelle reverses cell-surface and exosomal PD-L1 immunosuppression in tumors resistant to PD-L1 antibody therapy
Sustained replenishment of cell-surface and exosomal PD-L1 has been believed as the most important factor in the progression of PD-L1 antibody therapy resistance. Given that direct genetic blockade of PD-L1 may lead to unintended consequences and that posttranslational modifications (PTMs) are often used as pharmacological targets of cancer therapy, approaches targeting PD-L1 PTMs show great potential as new therapeutic paradigms. Palmitoylation has emerged as a critical PTM for modulating PD-L1 stability and distribution. In this work, it is found that disruption of palmitoylation by 2-bromopalmitate (2-BP) dual-impaired PD-L1 on the cell surface and exosomes. An amphiphilic TME-responsive micelle was fabricated to efficiently deliver 2-BP and the chemotherapeutic agent cisplatin to tumor milieu. The composite formulation unifying elimination of cell-surface and exosomal PD-L1 with chemotherapy synergistically relieved immunosuppression in the tumor bed and draining lymph node, thereby dramatically restraining growth, postsurgical relapse, and metastasis in melanoma resistant to PD-L1 antibody therapy. Moreover, the formulation elicits potent T cell memory responses for long-term protection against tumor rechallenge. In summary, our study takes advantage of an amphiphilic nanoformula combination of a posttranslational modifier and chemotherapy to target tumors resistant to PD-L1 antibody therapy, and paves a new path for multimodal cancer treatment.
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.