{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T18:33:52Z","timestamp":1786732432332,"version":"build-2736575974"},"reference-count":58,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1946202"],"award-info":[{"award-number":["1946202"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM113123"],"award-info":[{"award-number":["P20GM113123"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["U54GM128729"],"award-info":[{"award-number":["U54GM128729"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM103442"],"award-info":[{"award-number":["P20GM103442"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Tumor-associated macrophage (TAM) infiltration is a critical characteristic of triple-negative breast cancer (TNBC) related to drug resistance and poor prognosis. Integrating macrophages into TNBC spheroids is crucial to improve the accuracy of 3D\n                    <jats:italic>in vitro<\/jats:italic>\n                    models that mimic the complexity of the tumor microenvironment (TME) and assess treatment response. However, this remains challenging since the reciprocal effects of these two cell types on each other are not fully understood. In this study, we used the TNBC cell line, MDA-MB-231, and polarized M1-like or M2-like macrophages derived from THP-1 monocytes to establish 3D co-culture spheroids to examine bidirectional interactions between these cells and responses to chemotherapy. Drug efficacy, epithelial-mesenchymal transition (EMT) in cancer cells, macrophage phenotypes, and RNA sequencing, including pathway enrichment analysis, were performed in 3D spheroids. CIBERSORTx deconvolution of RNA sequencing results facilitated the separation of cell types within mixtures to estimate their corresponding cell fractions. We observed that M2 macrophages increased the viability of MDA-MB-231 cells in 3D spheroids, while both M1 and M2 macrophages increased the chemosensitivity of 3D spheroids to doxorubicin and paclitaxel. Interestingly, instead of maintaining their phenotypes, both M1 and M2 macrophages lost some polarization and formed a mixed M1-M2 phenotype when co-cultured with MDA-MB-231 cells in 3D spheroids, a phenomenon further supported by RNA-seq deconvolution analysis. However, the fraction of M1-like macrophages shifting to M2-like was much lower than the fraction of M2-like macrophages shifting to M1-like in the 3D co-cultures. Compared with 2D cultures, an expected mesenchymal transition, numerous differentially expressed genes (DEGs) and various pathways, including both tumor-promoting and tumor-suppressing genes, were observed in 3D spheroid MDA-MB-231 cells. However, both M1- and M2-like macrophages induced only partial EMT phenotype changes of cancer cells in co-cultures. Furthermore, a coexistence of pro-inflammatory and anti-inflammatory DEGs was observed in both M1 and M2-like co-cultured cancer spheroids. In conclusion, our findings present an effective 3D co-culture system of breast cancer cells and integrated macrophages for studying dynamic cellular phenotype changes and reciprocal interactions in a heterogeneous environment to mimic aspects of the TME and enhance the accuracy of preclinical\n                    <jats:italic>in vitro<\/jats:italic>\n                    treatment response studies.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0356198","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T17:55:56Z","timestamp":1786730156000},"page":"e0356198","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bidirectional phenotypic transition in macrophages influences triple-negative breast cancer cell immune evasive patterns and response to chemotherapies in a co-culture spheroid model"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5048-1564","authenticated-orcid":true,"given":"Chen","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3146-9699","authenticated-orcid":true,"given":"Brett A.","family":"McGregor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junguk","family":"Hur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8671-5880","authenticated-orcid":true,"given":"Colin K.","family":"Combs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"issue":"3","key":"pone.0356198.ref001","article-title":"Evaluation of lncRNAs as Potential Biomarkers for Diagnosis of Metastatic Triple-Negative Breast Cancer through Bioinformatics and Machine Learning","volume":"22","author":"S Soleimani","year":"2024","journal-title":"Iran J Biotechnol"},{"key":"pone.0356198.ref002","unstructured":"World Health Organization. Breast cancer. https:\/\/www.who.int\/newsroom\/fact-sheets\/detail\/breast-cancer Accessed 2024 March 13."},{"issue":"2","key":"pone.0356198.ref003","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s00404-015-3859-y","article-title":"An overview of triple-negative breast cancer","volume":"293","author":"P Kumar","year":"2016","journal-title":"Arch Gynecol Obstet"},{"issue":"4","key":"pone.0356198.ref004","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.cpet.2023.04.002","article-title":"Molecular Classification of Breast Cancer","volume":"18","author":"M Roy","year":"2023","journal-title":"PET Clin"},{"issue":"8","key":"pone.0356198.ref005","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.3390\/cancers14081881","article-title":"Stress in Metastatic Breast Cancer: To the Bone and Beyond","volume":"14","author":"C Louren\u00e7o","year":"2022","journal-title":"Cancers (Basel)"},{"issue":"3","key":"pone.0356198.ref006","doi-asserted-by":"crossref","first-page":"237","DOI":"10.21147\/j.issn.1000-9604.2017.03.10","article-title":"Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance","volume":"29","author":"T Yu","year":"2017","journal-title":"Chin J Cancer Res"},{"issue":"8","key":"pone.0356198.ref007","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1038\/nm.3909","article-title":"The prognostic landscape of genes and infiltrating immune cells across human cancers","volume":"21","author":"AJ Gentles","year":"2015","journal-title":"Nat Med"},{"key":"pone.0356198.ref008","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3389\/fonc.2018.00049","article-title":"Targeting Macrophages in Cancer: From Bench to Bedside","volume":"8","author":"AR Poh","year":"2018","journal-title":"Front Oncol"},{"key":"pone.0356198.ref009","first-page":"948098","article-title":"Macrophages in tumor microenvironments and the progression of tumors","volume":"2012","author":"N-B Hao","year":"2012","journal-title":"Clin Dev Immunol"},{"key":"pone.0356198.ref010","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.ctrv.2018.08.010","article-title":"Tumor-associated macrophages in breast cancer: Innocent bystander or important player?","volume":"70","author":"S-Q Qiu","year":"2018","journal-title":"Cancer Treat Rev"},{"issue":"11","key":"pone.0356198.ref011","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1016\/j.apsb.2020.04.004","article-title":"The role of tumor-associated macrophages (TAMs) in tumor progression and relevant advance in targeted therapy","volume":"10","author":"Q Yang","year":"2020","journal-title":"Acta Pharm Sin B"},{"key":"pone.0356198.ref012","doi-asserted-by":"crossref","first-page":"9188","DOI":"10.1038\/srep09188","article-title":"Characterization of macrophage--cancer cell crosstalk in estrogen receptor positive and triple-negative breast cancer","volume":"5","author":"M Hollm\u00e9n","year":"2015","journal-title":"Sci Rep"},{"key":"pone.0356198.ref013","doi-asserted-by":"crossref","first-page":"1513421","DOI":"10.3389\/fimmu.2024.1513421","article-title":"Patterns of immune evasion in triple-negative breast cancer and new potential therapeutic targets: a review","volume":"15","author":"L Serrano Garc\u00eda","year":"2024","journal-title":"Front Immunol"},{"issue":"7","key":"pone.0356198.ref014","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0182039","article-title":"Pancreatic cancer cell\/fibroblast co-culture induces M2 like macrophages that influence therapeutic response in a 3D model","volume":"12","author":"J Kuen","year":"2017","journal-title":"PLoS One"},{"key":"pone.0356198.ref015","doi-asserted-by":"crossref","first-page":"782766","DOI":"10.3389\/fonc.2021.782766","article-title":"Advancements in 3D Cell Culture Systems for Personalizing Anti-Cancer Therapies","volume":"11","author":"AMK Law","year":"2021","journal-title":"Front Oncol"},{"issue":"8","key":"pone.0356198.ref016","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1007\/s10529-016-2035-1","article-title":"Three-dimensional perfused tumour spheroid model for anti-cancer drug screening","volume":"38","author":"X Wan","year":"2016","journal-title":"Biotechnol Lett"},{"issue":"6","key":"pone.0356198.ref017","doi-asserted-by":"crossref","first-page":"100792","DOI":"10.1016\/j.crmeth.2024.100792","article-title":"A co-culture system of macrophages with breast cancer tumoroids to study cell interactions and therapeutic responses","volume":"4","author":"A Raffo-Romero","year":"2024","journal-title":"Cell Rep Methods"},{"key":"pone.0356198.ref018","doi-asserted-by":"crossref","first-page":"5395","DOI":"10.2147\/OTT.S249756","article-title":"Characterization of Triple-Negative Breast Cancer MDA-MB-231 Cell Spheroid Model","volume":"13","author":"Z Huang","year":"2020","journal-title":"Onco Targets Ther"},{"key":"pone.0356198.ref019","unstructured":"Andrews S. FastQC: A quality control tool for high throughput sequence data. 2010."},{"issue":"15","key":"pone.0356198.ref020","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: a flexible trimmer for Illumina sequence data","volume":"30","author":"AM Bolger","year":"2014","journal-title":"Bioinformatics"},{"issue":"8","key":"pone.0356198.ref021","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkz114","article-title":"The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads","volume":"47","author":"Y Liao","year":"2019","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"pone.0356198.ref022","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1101\/gr.275193.120","article-title":"Rapid and accurate alignment of nucleotide conversion sequencing reads with HISAT-3N","volume":"31","author":"Y Zhang","year":"2021","journal-title":"Genome Res"},{"issue":"12","key":"pone.0356198.ref023","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"MI Love","year":"2014","journal-title":"Genome Biol"},{"key":"pone.0356198.ref024","unstructured":"Kevin B, Sharmila R, Myles L. EnhancedVolcano: Publication-ready volcano plots with enhanced colouring and labeling. 2024."},{"key":"pone.0356198.ref025","unstructured":"Kolde R. Pheatmap: Pretty heatmaps. 2018."},{"issue":"7","key":"pone.0356198.ref026","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","author":"AM Newman","year":"2019","journal-title":"Nat Biotechnol"},{"issue":"1","key":"pone.0356198.ref027","doi-asserted-by":"crossref","DOI":"10.1093\/genetics\/iyad031","article-title":"The Gene Ontology knowledgebase in 2023","volume":"224","author":"Gene Ontology Consortium","year":"2023","journal-title":"Genetics"},{"issue":"1","key":"pone.0356198.ref028","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology","volume":"25","author":"M Ashburner","year":"2000","journal-title":"Nat Genet"},{"key":"pone.0356198.ref029","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkae909","article-title":"KEGG: biological systems database as a model of the real world","volume":"53","author":"M Kanehisa","year":"2025","journal-title":"Nucleic Acids Res"},{"issue":"11","key":"pone.0356198.ref030","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1002\/pro.3715","article-title":"Toward understanding the origin and evolution of cellular organisms","volume":"28","author":"M Kanehisa","year":"2019","journal-title":"Protein Sci"},{"issue":"1","key":"pone.0356198.ref031","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"28","author":"M Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"pone.0356198.ref032","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkac963","article-title":"KEGG for taxonomy-based analysis of pathways and genomes","volume":"51","author":"M Kanehisa","year":"2023","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pone.0356198.ref033","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12859-017-1559-2","article-title":"Reactome pathway analysis: a high-performance in-memory approach","volume":"18","author":"A Fabregat","year":"2017","journal-title":"BMC Bioinformatics"},{"key":"pone.0356198.ref034","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkad1025","article-title":"The Reactome Pathway Knowledgebase 2024","volume":"52","author":"M Milacic","year":"2024","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"pone.0356198.ref035","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"VK Mootha","year":"2003","journal-title":"Nat Genet"},{"issue":"2","key":"pone.0356198.ref036","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.canlet.2014.06.022","article-title":"Enriched CD44(+)\/CD24(-) population drives the aggressive phenotypes presented in triple-negative breast cancer (TNBC)","volume":"353","author":"F Ma","year":"2014","journal-title":"Cancer Lett"},{"key":"pone.0356198.ref037","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41523-019-0133-7","article-title":"If we build it they will come: targeting the immune response to breast cancer","volume":"5","author":"ME Gatti-Mays","year":"2019","journal-title":"NPJ Breast Cancer"},{"key":"pone.0356198.ref038","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1186\/1471-2407-12-306","article-title":"The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients","volume":"12","author":"C Medrek","year":"2012","journal-title":"BMC Cancer"},{"issue":"10","key":"pone.0356198.ref039","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1038\/ni.1937","article-title":"Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm","volume":"11","author":"SK Biswas","year":"2010","journal-title":"Nat Immunol"},{"issue":"1","key":"pone.0356198.ref040","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.bbcan.2017.10.007","article-title":"Triple negative breast cancer: Key role of Tumor-Associated Macrophages in regulating the activity of anti-PD-1\/PD-L1 agents","volume":"1869","author":"M Santoni","year":"2018","journal-title":"Biochim Biophys Acta Rev Cancer"},{"issue":"6","key":"pone.0356198.ref041","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1158\/1541-7786.MCR-11-0604","article-title":"Basal-like breast cancer cells induce phenotypic and genomic changes in macrophages","volume":"10","author":"DA Stewart","year":"2012","journal-title":"Mol Cancer Res"},{"issue":"8","key":"pone.0356198.ref042","article-title":"Triple-negative breast cancer influences a mixed M1\/M2 macrophage phenotype associated with tumor aggressiveness","volume":"17","author":"KCS Pe","year":"2022","journal-title":"PLoS One"},{"issue":"1","key":"pone.0356198.ref043","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1186\/s13046-018-0860-x","article-title":"Anti-inflammatory signaling by mammary tumor cells mediates prometastatic macrophage polarization in an innovative intraductal mouse model for triple-negative breast cancer","volume":"37","author":"J Steenbrugge","year":"2018","journal-title":"J Exp Clin Cancer Res"},{"key":"pone.0356198.ref044","doi-asserted-by":"crossref","first-page":"107682","DOI":"10.1016\/j.intimp.2021.107682","article-title":"Macrophage balance fraction determines the degree of immunosuppression and metastatic ability of breast cancer","volume":"97","author":"C Wang","year":"2021","journal-title":"Int Immunopharmacol"},{"issue":"2","key":"pone.0356198.ref045","doi-asserted-by":"crossref","first-page":"022001","DOI":"10.1088\/1758-5082\/6\/2\/022001","article-title":"Three-dimensional in vitro cancer models: a short review","volume":"6","author":"C Wang","year":"2014","journal-title":"Biofabrication"},{"issue":"9","key":"pone.0356198.ref046","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1089\/adt.2015.662","article-title":"Production of Uniform 3D Microtumors in Hydrogel Microwell Arrays for Measurement of Viability, Morphology, and Signaling Pathway Activation","volume":"13","author":"M Singh","year":"2015","journal-title":"Assay Drug Dev Technol"},{"key":"pone.0356198.ref047","doi-asserted-by":"crossref","first-page":"247","DOI":"10.4172\/2155-9872.1000249","article-title":"Three-Dimensional (3D) Cell Cultures in Cell-based Assays for in-vitro Evaluation of Anticancer Drugs","volume":"6","author":"AF Adcock","year":"2015","journal-title":"J Anal Bioanal Tech"},{"issue":"5","key":"pone.0356198.ref048","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s12032-022-01670-7","article-title":"Tumor-associated macrophages of the M1\/M2 phenotype are involved in the regulation of malignant biological behavior of breast cancer cells through the EMT pathway","volume":"39","author":"Z Chen","year":"2022","journal-title":"Med Oncol"},{"key":"pone.0356198.ref049","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s10911-016-9359-2","article-title":"Generation of Multicellular Breast Cancer Tumor Spheroids: Comparison of Different Protocols","volume":"21","author":"K Froehlich","year":"2016","journal-title":"J Mammary Gland Biol Neoplasia"},{"issue":"2","key":"pone.0356198.ref050","doi-asserted-by":"crossref","first-page":"188","DOI":"10.7240\/jeps.1631660","article-title":"Correlation between spheroid formation ability and reported invasiveness of HEK-293, HT-29, MDA-MB-231, and HeLa cancer cell lines in commercial well plates","volume":"37","author":"Ismail E\u015f","year":"2025","journal-title":"International Journal of Advances in Engineering and Pure Sciences"},{"issue":"5","key":"pone.0356198.ref051","doi-asserted-by":"crossref","DOI":"10.1186\/bcr2945","article-title":"Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL","volume":"13","author":"L Piggott","year":"2011","journal-title":"Breast Cancer Res"},{"issue":"1","key":"pone.0356198.ref052","doi-asserted-by":"crossref","first-page":"23","DOI":"10.7150\/ijms.22002","article-title":"Effects of \u03b1-Mangostin on Viability, Growth and Cohesion of Multicellular Spheroids Derived from Human Breast Cancer Cell Lines","volume":"15","author":"G Scolamiero","year":"2018","journal-title":"Int J Med Sci"},{"issue":"8","key":"pone.0356198.ref053","doi-asserted-by":"crossref","first-page":"415","DOI":"10.3390\/toxics10080415","article-title":"Morphometrical, morphological, and immunocytochemical characterization of a tool for cytotoxicity research: 3D cultures of breast cell lines grown in ultra-low attachment plates","volume":"10","author":"F Malh\u00e3o","year":"2022","journal-title":"Toxics"},{"issue":"6","key":"pone.0356198.ref054","first-page":"1403","article-title":"Diversity of cell-mediated adhesions in breast cancer spheroids","volume":"31","author":"A Ivascu","year":"2007","journal-title":"Int J Oncol"},{"issue":"1","key":"pone.0356198.ref055","article-title":"Macrophage subtypes inhibit breast cancer proliferation in culture","volume":"36","author":"SRS Varady","year":"2025","journal-title":"Molecular Biology of the Cell"},{"key":"pone.0356198.ref056","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1046\/j.1365-2184.36.s.1.6.x","article-title":"Stem cells in normal breast development and breast cancer","author":"G Dontu","year":"2003","journal-title":"Cell Prolif"},{"issue":"11","key":"pone.0356198.ref057","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1136\/jcp.2011.090456","article-title":"Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype","volume":"64","author":"S Ricardo","year":"2011","journal-title":"J Clin Pathol"},{"issue":"8","key":"pone.0356198.ref058","article-title":"Evaluation of CD44 \/CD24- and aldehyde dehydrogenase enzyme markers in cancer stem cells as prognostic indicators for triple-negative breast cancer","volume":"14","author":"L Escudero Mendez","year":"2022","journal-title":"Cureus"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0356198","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T17:56:11Z","timestamp":1786730171000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0356198"}},"subtitle":[],"editor":[{"given":"Xiaozhe","family":"Han","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":58,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0356198","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]}}}