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Local release of 5-FU and STFM/R, followed by STFM/R degradation, induces iron-overload ferroptosis via Fe2+, while liberated Mn2+ cooperates with R848 to activate cGAS-STING signaling. This drives dendritic cell maturation and M2-to-M1 macrophage repolarization, improving delivery efficacy, remodeling immunosuppressive microenvironments, and enhancing chemotherapeutic outcomes while minimizing systemic toxicity.",{"@graph":14,"@context":72},[15,34,55],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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is the main therapeutic strategy described in the article?","Question",{"text":62,"@type":63},"A nanofiber-based drug delivery system is engineered to synergistically induce ferroptosis and potentiate immunotherapy for melanoma treatment.","Answer",{"name":65,"@type":60,"acceptedAnswer":66},"How does the system trigger ferroptosis?",{"text":67,"@type":63},"After STFM/R degradation, Fe2+ released through iron overload drives ferroptosis at the tumor site.",{"name":69,"@type":60,"acceptedAnswer":70},"Which mechanism enhances antitumor immunity beyond ferroptosis?",{"text":71,"@type":63},"Mn2+ released from STFM/R synergizes with resiquimod (R848) to activate the cGAS-STING signaling pathway, promoting dendritic cell maturation and M2-to-M1 macrophage 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Ferroptosis and Stimulate Antitumor Immunity for Melanoma Therapy  \nMingyang Li, Rongrong Li, Baotong Xu, Yuhan Lian, Chenyu Yang, Jingwen Li, Junhao Liang, Linhan Ding, Dongsheng Zhang, Jing Guo,* and Xiao Fu*  \nMelanoma, a highly aggressive and therapy-resistant cutaneous malignancy, presents formidable clinical challenges owing to its propensity for early metastasis and frequent postoperative recurrence. Here, a nanofiber-based drug delivery system (5F/STFM/R-ES) is developed that synergistically induces ferroptosis and potentiates immunotherapy to inhibit melanoma growth and reduce the risk of metastasis and recurrence. To this end, mesoporous silica nanoparticles encapsulating resiquimod (R848) are surface-coated with Fe/Mn-based metal-polyphenol networks (TFM) to form STFM/R. Subsequently, STFM/R is electrospun into 5-fluorouracil-loaded nanofibers. When applied to the tumor site, 5-fluorouracil and STFM/R are released. Following the degradation of STFM/R, the release ofFe2 + triggered ferroptosis through iron overload, while the simultaneous liberation of Mn2 + synergizes with R848 to activate the cGAS-STING signaling pathway. This multifunctional strategy promotes the maturation of dendritic cells andrepolarizes tumor-associated macrophages from M2 to M1. The in vivo and in vitro evaluations reveal that 5F/STFM/R-ES significantly improves delivery efficacy, remodels the immunosuppressive tumor microenvironment, and enhances the therapeutic efficacy of chemotherapeutics. The localized delivery strategy of the platform minimizes systemic toxicity while achieving combinatorial therapeutic effects, highlighting its potential for personalized melanoma therapy.  \ncontributes to over 80% of fatalities. [2,3] Although the clinical translation of molecularly targeted agents and immunotherapeutic regimens has led to substantial advancesin melanoma therapy, a number of patients still fail to attain optimal therapeutic outcomes, owing to issues such as treatment resistance and recurrence. [4,5]  \nThe development of immunotherapy has opened new avenues for cancer treatment, and the field of cancer immunotherapy is experiencing continuous rejuvenation. [6] The purpose of immunotherapy is to activate the host immune system to recognize and kill the malignant tumors. [7] Several types of cancers, especially melanoma, have demonstrated a prolonged clinical response to immunotherapy.[8] Various immunotherapies strategies such as cancer vaccines, adoptive cell transfer (ACTs), immune checkpoint inhibitors (ICIs), and oncolytic virus therapy (OVTs) have shown promising clinical outcomes. [9,10] As a novel and critical innate immune signaling pathway, the cGAS-STING pathway is triggered by nucleic acids and interacts with other immune responses, thereby playing an essential role in cancer immunoregulation. [11]  \n1. Introduction  \nMelanoma is a highly aggressive cancer with increasing incidence. [1] It comprises only 1% of skin cancer cases but  \ncGAS efficiently identifies all free cytoplasmic DNA originating from both self-and foreign sources such as viruses, dead cells, tumor cells, and microorganisms. [12] The cGAS synthesizes cyclic guanosine monophosphate-adenosine monophos-  \nM. Li, R. Li, B. Xu, Y. Lian, C. Yang, J. Li, J. Liang, L. Ding, D. Zhang, X. Fu Department ofStomatology  \nShandong Provincial Hospital Affiliated to Shandong First Medical University  \nNo.324 Jingwuweiqi Road, Huaiyin District, Jinan, Shandong Province 250021, P. R. China  \nE-mail: [fuxiao@sdfmu.edu.cn](fuxiao@sdfmu.edu.cn)  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202508753](https://doi.org/10.1002/advs.202508753)[ ](https://doi.org/10.1002/advs.202508753)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Comm","cbCaiieuEo7ZVaEb","https://ap.wps.com/l/cbCaiieuEo7ZVaEb","pdf",5766765,15,"English","# Introduction\n## Immunotherapy and antitumor immunity\n## cGAS-STING pathway and immune activation\n# Nanofiber-based delivery strategy (STFM/R and 5F/STFM/R-ES)","[{\"question\":\"What is the main therapeutic strategy described in the article?\",\"answer\":\"A nanofiber-based drug delivery system is engineered to synergistically induce ferroptosis and potentiate immunotherapy for melanoma treatment.\"},{\"question\":\"How does the system trigger ferroptosis?\",\"answer\":\"After STFM/R degradation, Fe2+ released through iron overload drives ferroptosis at the tumor site.\"},{\"question\":\"Which mechanism enhances antitumor immunity beyond ferroptosis?\",\"answer\":\"Mn2+ released from STFM/R synergizes with resiquimod (R848) to activate the cGAS-STING signaling pathway, promoting dendritic cell maturation and M2-to-M1 macrophage repolarization.\"}]","Nanoparticle-Modified Nanofibers Induce Ferroptosis and Stimulate Antitumor Immunity for Melanoma Therapy | PDF",1790689188,38]