{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:12:57Z","timestamp":1791213177508,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T00:00:00Z","timestamp":1778889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Paceline","award":["IGPCT0016"],"award-info":[{"award-number":["IGPCT0016"]}]},{"name":"Paceline","award":["IGPP0048"],"award-info":[{"award-number":["IGPP0048"]}]},{"name":"Georgia Cancer Center"},{"id":[{"id":"https:\/\/ror.org\/0457d9w72","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/objective: Approximately 90% of breast cancer-related deaths result from recurrence and metastasis. Emerging evidence indicates that tumor recurrence, invasion, and metastatic spread are strongly influenced by both the tumor microenvironment (TME) and the metastatic niche. M2 macrophages promote immune suppression, inhibit inflammation, and facilitate epithelial-to-mesenchymal transition, invasion, neovascularization, and tumor progression. These phenomena are particularly pronounced in triple-negative breast cancer (TNBC). The objectives of this study were to develop engineered exosomes to selectively deplete CD206+ M2 macrophages from the TME to delay the growth of primary tumors and distal metastasis and enhance overall survival. Methods: Engineered exosomes were developed using our invented platform to selectively target and deplete alternatively activated CD206+ M2 macrophages in primary and metastatic TMEs via antibody-dependent cell-mediated cytotoxicity (ADCC). The engineered exosomes were characterized for size, zeta potential, and successful incorporation of targeting peptides and proteins. Whole-body and tumor-specific biodistribution were assessed. In vitro and in vivo experiments were conducted to evaluate targeting specificity. Toxicity and immunogenicity were examined in immunocompetent animal models. Two treatment paradigms were employed. Results: Engineered exosomes containing M2 macrophage-targeting peptides and Fc-mIgG2b were successfully made, and no significant size difference was observed between the engineered and control exosomes. Both in vitro and in vivo studies confirmed the specificity of the engineered exosomes. Biodistribution studies showed no significant uptake or retention by the resident macrophages in the lung and liver. No significant immune activation, based on cytokine profiling, or organ-specific toxicity was observed in immunocompetent models. Flow cytometry studies using splenocytes showed significant depletion of M2 macrophages following treatments with engineered exosomes; however, no effect on the distribution of T cells was observed. M2-targeting engineered exosomes significantly delayed the post-resection recurrence and metastasis of tumors, and improved animal survival. Conclusions: These findings support the potential of precision exosome-based strategies for enhancing therapeutic outcomes in breast cancer.<\/jats:p>","DOI":"10.3390\/cancers18101619","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T08:56:27Z","timestamp":1779094587000},"page":"1619","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Therapeutically Engineering Exosomes to Target CD206+ M2 Macrophages to Prevent the Development of Primary Tumors and Distal Metastases in Breast Cancers"],"prefix":"10.3390","volume":"18","author":[{"given":"Mahrima","family":"Parvin","sequence":"first","affiliation":[{"name":"Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30921, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7039-1911","authenticated-orcid":false,"given":"Ahmet","family":"Alptekin","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30921, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sawaiz","family":"Kashif","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30921, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fowzia A.","family":"Selina","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30921, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mst Anika","family":"Bushra","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30921, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Syam","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30921, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1056-4910","authenticated-orcid":false,"given":"Mohammad H.","family":"Rashid","sequence":"additional","affiliation":[{"name":"Department of Medicine, Carle Illinois College of Medicine, Urbana, IL 61801, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9549-6296","authenticated-orcid":false,"given":"Alicia","family":"Arnold","sequence":"additional","affiliation":[{"name":"Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santhakumar","family":"Manicassamy","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30921, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0719-5862","authenticated-orcid":false,"given":"Hasan","family":"Korkaya","sequence":"additional","affiliation":[{"name":"Karmanos Cancer Institute, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2902-3671","authenticated-orcid":false,"given":"Ali S.","family":"Arbab","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30921, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,16]]},"reference":[{"key":"ref_1","first-page":"23","article-title":"Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment","volume":"1865","author":"Lahmar","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/s41591-018-0014-x","article-title":"Understanding the tumor immune microenvironment (TIME) for effective therapy","volume":"24","author":"Binnewies","year":"2018","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Neophytou, C.M., Panagi, M., Stylianopoulos, T., and Papageorgis, P. (2021). The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities. Cancers, 13.","DOI":"10.3390\/cancers13092053"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41416-018-0327-z","article-title":"The clinical role of the TME in solid cancer","volume":"120","author":"Giraldo","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Khalaf, K., Hana, D., Chou, J.T.-T., Singh, C., Mackiewicz, A., and Kaczmarek, M. (2021). Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.656364"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s42255-020-00317-z","article-title":"Metabolites and the tumour microenvironment: From cellular mechanisms to systemic metabolism","volume":"3","author":"Elia","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/s41588-022-01041-y","article-title":"Breast tumor microenvironment structures are associated with genomic features and clinical outcome","volume":"54","author":"Danenberg","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: In vivo veritas","volume":"122","author":"Sica","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/0470856734.ch10","article-title":"Infiltration of tumours by macrophages and dendritic cells: Tumour-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes","volume":"256","author":"Mantovani","year":"2004","journal-title":"Novartis Found. Symp."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.cyto.2008.07.014","article-title":"Cytokines as a key component of cancer-related inflammation","volume":"43","author":"Germano","year":"2008","journal-title":"Cytokine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.canlet.2008.03.028","article-title":"Cancer related inflammation: The macrophage connection","volume":"267","author":"Sica","year":"2008","journal-title":"Cancer Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.2147\/IJGM.S461144","article-title":"Unveiling the Impact of MRC1 on Immune Infiltration and Patient\u2019s Prognosis: A Pan-Cancer Analysis Based on Single-Cell and Bulk Sequencing","volume":"17","author":"Wu","year":"2024","journal-title":"Int. J. Gen. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Debacker, J.M., Gondry, O., Lahoutte, T., Keyaerts, M., and Huvenne, W. (2021). The Prognostic Value of CD206 in Solid Malignancies: A Systematic Review and Meta-Analysis. Cancers, 13.","DOI":"10.3390\/cancers13143422"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.it.2022.04.008","article-title":"Macrophage diversity in cancer revisited in the era of single-cell omics","volume":"43","author":"Ma","year":"2022","journal-title":"Trends Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gordon, S., and Pl\u00fcddemann, A. (2017). Tissue macrophages: Heterogeneity and functions. BMC Biol., 15.","DOI":"10.1186\/s12915-017-0392-4"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nrm.2017.125","article-title":"Shedding light on the cell biology of extracellular vesicles","volume":"19","author":"Raposo","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"011503","DOI":"10.1063\/1.5087122","article-title":"Challenges and opportunities in exosome research\u2014Perspectives from biology, engineering, and cancer therapy","volume":"3","author":"Li","year":"2019","journal-title":"APL Bioeng."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/ncb1596","article-title":"Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells","volume":"9","author":"Valadi","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/sj.embor.7400945","article-title":"RNA channelling by the archaeal exosome","volume":"8","author":"Lorentzen","year":"2007","journal-title":"EMBO Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3365","DOI":"10.1242\/jcs.113.19.3365","article-title":"Exosome: From internal vesicle of the multivesicular body to intercellular signaling device","volume":"19","author":"Denzer","year":"2000","journal-title":"J. Cell Sci."},{"key":"ref_21","first-page":"480","article-title":"Role of Exosome Shuttle RNA in Cell-to-Cell Communication","volume":"38","author":"Zhang","year":"2016","journal-title":"Zhongguo Yi Xue Ke Xue Yuan Xue Bao"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1146\/annurev-cellbio-101512-122326","article-title":"Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles","volume":"30","author":"Colombo","year":"2014","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1172\/JCI81135","article-title":"The biology and function of exosomes in cancer","volume":"126","author":"Kalluri","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/nrd3978","article-title":"Extracellular vesicles: Biology and emerging therapeutic opportunities","volume":"12","author":"Andaloussi","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"30087","DOI":"10.3402\/jev.v4.30087","article-title":"Applying extracellular vesicles based therapeutics in clinical trials\u2014An ISEV position paper","volume":"4","author":"Lener","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ijpharm.2017.02.038","article-title":"Exosomes as novel bio-carriers for gene and drug delivery","volume":"521","author":"Jiang","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nbt.1807","article-title":"Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes","volume":"29","author":"Seow","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.addr.2012.08.008","article-title":"Exosomes for targeted siRNA delivery across biological barriers","volume":"65","author":"Lakhal","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1038\/nprot.2012.131","article-title":"Exosome-mediated delivery of siRNA in vitro and in vivo","volume":"7","author":"Lee","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s12943-019-0991-5","article-title":"Exosomes: Composition, biogenesis, and mechanisms in cancer metastasis and drug resistance","volume":"18","author":"Mashouri","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1016\/j.bbagen.2018.06.003","article-title":"Engineered exosomes: A new promise for the management of musculoskeletal diseases","volume":"1862","author":"Bellavia","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA) Gen. Subj."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.ymthe.2017.03.030","article-title":"Engineered Exosomes as Vehicles for Biologically Active Proteins","volume":"25","author":"Sterzenbach","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/aps.2017.12","article-title":"Engineering exosomes as refined biological nanoplatforms for drug delivery","volume":"38","author":"Luan","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.biomaterials.2017.10.012","article-title":"Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy","volume":"150","author":"Tian","year":"2018","journal-title":"Biomaterials"},{"key":"ref_35","unstructured":"Arbab, A., Rashid, M.H., Borin, T., and Ara, R. (2020). Engineered Exosomes to Detect and Deplete Pro-Tumorigenic Macrophages. (17\/083,124), U.S. Patent."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"102072","DOI":"10.1016\/j.nano.2019.102072","article-title":"Differential in vivo biodistribution of 131I-labeled exosomes from diverse cellular origins and its implication for theranostic application","volume":"21","author":"Rashid","year":"2019","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1900209","DOI":"10.1002\/adtp.201900209","article-title":"Generation of Novel Diagnostic and Therapeutic Exosomes to Detect and Deplete Protumorigenic M2 Macrophages","volume":"3","author":"Rashid","year":"2020","journal-title":"Adv. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"14655","DOI":"10.1038\/s41598-017-14709-x","article-title":"Precision Targeting of Tumor Macrophages with a CD206 Binding Peptide","volume":"7","author":"Scodeller","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1021\/acs.jpcb.8b11876","article-title":"Phage-Display-Derived Peptide Binds to Human CD206 and Modeling Reveals a New Binding Site on the Receptor","volume":"123","author":"Asciutto","year":"2019","journal-title":"J. Phys. Chem. B"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1038\/s41467-019-09015-1","article-title":"Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model","volume":"10","author":"Piranlioglu","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1179064417713197","DOI":"10.1177\/1179064417713197","article-title":"Suppression of Breast Cancer Metastasis Using Stapled Peptides Targeting the WASF Regulatory Complex","volume":"10","author":"Cowell","year":"2017","journal-title":"Cancer Growth Metastasis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.3892\/or.2021.7936","article-title":"Critical immunosuppressive effect of MDSCderived exosomes in the tumor microenvironment","volume":"45","author":"Rashid","year":"2021","journal-title":"Oncol. Rep."},{"key":"ref_43","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":"Qiu","year":"2018","journal-title":"Cancer Treat. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/s12032-014-0352-6","article-title":"Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10\/STAT3\/bcl-2 signaling pathway","volume":"32","author":"Yang","year":"2015","journal-title":"Med. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"14979","DOI":"10.1038\/ncomms14979","article-title":"Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade","volume":"8","author":"Ouzounova","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Borin, T.F., Shankar, A., Angara, K., Rashid, M.H., Jain, M., Iskander, A., Ara, R., Lebedyeva, I., Korkaya, H., and Achyut, B.R. (2017). HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178830"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.celrep.2017.03.038","article-title":"Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents","volume":"19","author":"Olson","year":"2017","journal-title":"Cell Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.ccell.2015.02.015","article-title":"Macrophages and therapeutic resistance in cancer","volume":"27","author":"Ruffell","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1084\/jem.20150295","article-title":"The interaction of anticancer therapies with tumor-associated macrophages","volume":"212","author":"Mantovani","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Sami, A., and Raza, A. (2024). Reprogramming the tumor microenvironment\u2014Macrophages emerge as key players in breast cancer immunotherapy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1457491"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11049","DOI":"10.1002\/cam4.5489","article-title":"Antitumor therapy for breast cancer: Focus on tumor-associated macrophages and nanosized drug delivery systems","volume":"12","author":"Zhan","year":"2023","journal-title":"Cancer Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"A252","DOI":"10.1158\/1535-7163.TARG-13-A252","article-title":"Abstract A252: A phase 1 study of ARRY-382, an oral inhibitor of colony-stimulating factor-1 receptor (CSF1R), in patients with advanced or metastatic cancers","volume":"12","author":"Bendell","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/j.ccr.2014.05.016","article-title":"Targeting Tumor-Associated Macrophages with Anti-CSF-1R Antibody Reveals a Strategy for Cancer Therapy","volume":"25","author":"Ries","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4064","DOI":"10.1038\/s41467-020-17914-x","article-title":"FGF2 alters macrophage polarization, tumour immunity and growth and can be targeted during radiotherapy","volume":"11","author":"Im","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1093\/annonc\/mdz163","article-title":"Phase I study of emactuzumab single agent or in combination with paclitaxel in patients with advanced\/metastatic solid tumors reveals depletion of immunosuppressive M2-like macrophages","volume":"30","author":"Italiano","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"eaax6337","DOI":"10.1126\/scitranslmed.aax6337","article-title":"Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses","volume":"12","author":"Jaynes","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"13242","DOI":"10.1038\/s41598-017-12829-y","article-title":"In vivo imaging of lung inflammation with neutrophil-specific 68Ga nano-radiotracer","volume":"7","author":"Pellico","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.exer.2005.06.010","article-title":"Genetic background determines susceptibility to experimental immune-mediated blepharoconjunctivitis: Comparison of Balb\/c and C57BL\/6 mice","volume":"82","author":"Fukushima","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1046\/j.0022-202x.2001.01665.x","article-title":"Expression and function of the mannose receptor CD206 on epidermal dendritic cells in inflammatory skin diseases","volume":"118","author":"Wollenberg","year":"2002","journal-title":"J. Investig. Dermatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/imm.12888","article-title":"Human dendritic cell subsets: An update","volume":"154","author":"Collin","year":"2018","journal-title":"Immunology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1324730","DOI":"10.1080\/20013078.2017.1324730","article-title":"Comprehensive toxicity and immunogenicity studies reveal minimal effects in mice following sustained dosing of extracellular vesicles derived from HEK293T cells","volume":"6","author":"Zhu","year":"2017","journal-title":"J. Extracell. Vesicles"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1007\/s12975-017-0599-2","article-title":"Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model","volume":"9","author":"Webb","year":"2018","journal-title":"Transl. Stroke Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"20230139","DOI":"10.1002\/EXP.20230139","article-title":"Unveiling the promise: Exosomes as game-changers in anti-infective therapy","volume":"4","author":"Chavda","year":"2024","journal-title":"Exploration"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"20240039","DOI":"10.1002\/EXP.20240039","article-title":"Engineered brain-targeting exosome for reprogramming immunosuppressive microenvironment of glioblastoma","volume":"5","author":"Yang","year":"2025","journal-title":"Exploration"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Alptekin, A., Khan, M.B., Parvin, M., Chowdhury, H., Kashif, S., Selina, F.A., Bushra, A., Kelleher, J., Ghosh, S., and Williams, D. (2025). Effects of low-intensity pulsed focal ultrasound-mediated delivery of endothelial progenitor-derived exosomes in tMCAo stroke. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1543133"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"A073","DOI":"10.1161\/str.57.suppl_1.A073","article-title":"Engineered Exosomes Carrying Rabies Viral Glycoprotein (RVG) and Neuroglobin (Ngb) Improved Stroke Outcome in Mouse Model of tMCAo","volume":"57","author":"Selina","year":"2026","journal-title":"Stroke"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Graziano, R.F., and Guyre, P.M. (2006). Antibody-dependent Cell-mediated Cytotoxicity (ADCC). eLS, Wiley Online Library.","DOI":"10.1038\/npg.els.0000498"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jaad.2019.03.049","article-title":"Rituximab therapy in patients with bullous pemphigoid: A retrospective study of 20 patients","volume":"81","author":"Polansky","year":"2019","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/art.20717","article-title":"Rituximab and Wegener\u2019s granulomatosis: Are B cells a target in vasculitis treatment?","volume":"52","author":"Sneller","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1158\/2326-6066.CIR-18-0266","article-title":"A Mechanism of Resistance to Antibody-Targeted Immune Attack","volume":"7","author":"Aldeghaither","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Wang, W., Erbe, A.K., Hank, J.A., Morris, Z.S., and Sondel, P.M. (2015). NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity in Cancer Immunotherapy. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00368"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nm.3560","article-title":"Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice","volume":"20","author":"Qin","year":"2014","journal-title":"Nat. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s12951-018-0403-9","article-title":"Recent advancements in the use of exosomes as drug delivery systems","volume":"16","author":"Bunggulawa","year":"2018","journal-title":"J. Nanobiotechnol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"182","DOI":"10.2174\/1566523214666141224100612","article-title":"Exosomes: A role for naturally occurring nanovesicles in cancer growth, diagnosis and treatment","volume":"15","author":"Srivastava","year":"2015","journal-title":"Curr. Gene Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/2045-8118-10-4","article-title":"Method for isolation and molecular characterization of extracellular microvesicles released from brain endothelial cells","volume":"10","author":"Haqqani","year":"2013","journal-title":"Fluids Barriers CNS"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1002\/bies.201100076","article-title":"Exosome nanotechnology: An emerging paradigm shift in drug delivery: Exploitation of exosome nanovesicles for systemic in vivo delivery of RNAi heralds new horizons for drug delivery across biological barriers","volume":"33","author":"Lakhal","year":"2011","journal-title":"Bioessays"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.addr.2012.07.002","article-title":"Exosomes are endogenous nanoparticles that can deliver biological information between cells","volume":"65","author":"Sun","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3625","DOI":"10.1021\/acs.molpharmaceut.8b00277","article-title":"Exosomes as a Drug Delivery System in Cancer Therapy: Potential and Challenges","volume":"15","author":"Kibria","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/prca.201400114","article-title":"Exosomes in bodily fluids are a highly stable resource of disease biomarkers","volume":"9","author":"Boukouris","year":"2015","journal-title":"Proteomics. Clin. Appl."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s13045-022-01335-y","article-title":"Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy","volume":"15","author":"Wang","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Peranzoni, E., Ingangi, V., Masetto, E., Pinton, L., and Marigo, I. (2020). Myeloid Cells as Clinical Biomarkers for Immune Checkpoint Blockade. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01590"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ejca.2023.03.040","article-title":"Shining a LIGHT on myeloid cell targeted immunotherapy","volume":"187","author":"Shuptrine","year":"2023","journal-title":"Eur. J. Cancer"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1158\/0008-5472.CAN-20-2990","article-title":"Macrophage-Based Approaches for Cancer Immunotherapy","volume":"81","author":"Anderson","year":"2021","journal-title":"Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e24130","DOI":"10.1200\/JCO.2018.36.15_suppl.e24130","article-title":"Tumor-associated macrophages: CD206 and CD68 expression and patient outcomes in locally advanced breast cancer","volume":"36","author":"Williams","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1158\/0008-5472.CAN-12-3542","article-title":"Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment","volume":"73","author":"Dijkgraaf","year":"2013","journal-title":"Cancer Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S1471-4906(02)02302-5","article-title":"Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes","volume":"23","author":"Mantovani","year":"2002","journal-title":"Trends Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1093\/intimm\/dxy064","article-title":"Identification and isolation of splenic tissue-resident macrophage sub-populations by flow cytometry","volume":"31","author":"Fujiyama","year":"2019","journal-title":"Int. Immunol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/10\/1619\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T09:18:24Z","timestamp":1779095904000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/10\/1619"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,16]]},"references-count":87,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cancers18101619"],"URL":"https:\/\/doi.org\/10.3390\/cancers18101619","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,16]]}}}