{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T10:23:50Z","timestamp":1791887030379,"version":"4.3.4"},"reference-count":76,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Metastasis induced by tumor immune escape has been implicated as one of the factors contributing to the aggressiveness of triple\u2010negative breast cancer. Macrophage type 1\u2010derived extracellular vesicles were isolated and combined with PLGA nanoparticles loaded with the TLR3 agonist poly I:C as a therapeutic strategy to investigate their antitumor activity by downregulating tumor immune escape in the tumor microenvironment (TME) of breast cancer in a murine model of orthotopic tumor growth. Tumors were evaluated by qRT\u2010PCR and immunohistochemistry. Cellular uptake and polarization of murine macrophages (RAW 264.7 cells) were analyzed In Vitro by immunofluorescence and flow cytometry, respectively. Furthermore, mouse survival, lymph node involvement, and metastasis were also evaluated. In the animal model, the combination therapy inhibited tumor progression through TME immunomodulation, leading to a reduction in primary tumor size (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) and metastasis, along with an extension in survival of 11 days. Importantly, both innate and adaptive immune responses were enhanced, as indicated by increased CD8 expression (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) and reduced PD\u2010L1 levels in the TME, as well as elevated CD11c expression in lymph nodes (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001). Likewise, the combination therapy suppressed tumor progression by reducing AKT1 expression (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) and increasing E\u2010cadherin expression (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). Based on these findings, the combination therapy functioned as a \u201cvaccine\u2010like immunomodulatory strategy,\u201d promoting TME immunomodulation and suppressing metastasis in a murine model of triple\u2010negative breast cancer.\n                  <\/jats:p>","DOI":"10.1002\/mc.70003","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T10:51:48Z","timestamp":1750762308000},"page":"1450-1461","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["M1 Macrophage Extracellular Vesicles and TLR3 Agonist Nanoparticles Down\u2010Regulate Immunosuppression and Metastasis via AKT\/TAM in Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","volume":"64","author":[{"given":"Shirley V. de Paiva","family":"Souza","sequence":"first","affiliation":[{"name":"Postgraduate Program in Health Science Federal University of Rio Grande do Norte (UFRN) Natal Brazil"},{"name":"Inflammation and Cancer Research Laboratory, Department of Morphology Federal University of Rio Grande do Norte (UFRN) Natal Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreza Concei\u00e7\u00e3o Veras","family":"Aguiar","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Health Science Federal University of Rio Grande do Norte (UFRN) Natal Brazil"},{"name":"Inflammation and Cancer Research Laboratory, Department of Morphology Federal University of Rio Grande do Norte (UFRN) Natal Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth Costa S. de","family":"Albuquerque","sequence":"additional","affiliation":[{"name":"Inflammation and Cancer Research Laboratory, Department of Morphology Federal University of Rio Grande do Norte (UFRN) Natal Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Eich","sequence":"additional","affiliation":[{"name":"Translational Nanobiomaterials and Imaging (TNI) Group, Department of Radiology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis J.","family":"Cruz","sequence":"additional","affiliation":[{"name":"Translational Nanobiomaterials and Imaging (TNI) Group, Department of Radiology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Lara","sequence":"additional","affiliation":[{"name":"Translational Nanobiomaterials and Imaging (TNI) Group, Department of Radiology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Jorquera\u2010Cordero","sequence":"additional","affiliation":[{"name":"Department of Orthopedics University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raelle Ferreira","family":"Gomes","sequence":"additional","affiliation":[{"name":"Department of Organic and Inorganic Chemistry Federal University of Cear\u00e1, UFC Fortaleza Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina C\u00e9lia Monteiro de","family":"Paula","sequence":"additional","affiliation":[{"name":"Department of Organic and Inorganic Chemistry Federal University of Cear\u00e1, UFC Fortaleza Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemayre S.","family":"Freire","sequence":"additional","affiliation":[{"name":"Department of Physics Federal University of Cear\u00e1 Fortaleza Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"de Ara\u00fajo J\u00fanior Raimundo Fernandes","family":"de Ara\u00fajoJ\u00fanior","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Health Science Federal University of Rio Grande do Norte (UFRN) Natal Brazil"},{"name":"Inflammation and Cancer Research 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