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Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among women, and resistance to chemotherapy remains a major clinical challenge. Although doxorubicin is widely used, its efficacy is limited by chemoresistance. Neutrophil extracellular traps (NETs), web-like structures composed of DNA and proteins released by activated neutrophils, have been implicated in tumor progression and metastasis; however, their role in chemoresistance remains poorly understood. Here, we investigated the impact of NETs on doxorubicin resistance in human breast cancer cell lines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>NETs were isolated from healthy donor blood and used to treat tumor cell lines (MCF7, T47D, and MDA-MB-231) prior to chemotherapy exposure. Cell viability and clonogenic potential were assessed by MTT and colony formation assays, while apoptotic signaling and AKT activation were evaluated by qPCR and Western blot. Pathway involvement was investigated using pharmacological inhibitors of PI3K, AKT, and NF-\u03baB and siRNA-mediated AKT1 knockdown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NETs were not cytotoxic but significantly increased clonogenic capacity and conferred resistance to doxorubicin. This effect was independent of the DNA scaffold and abolished by heat denaturation, implicating heat-labile, NET-associated components (most likely proteins) rather than the DNA backbone. NET exposure downregulated the pro-apoptotic factor BAX and upregulated the anti-apoptotic factor BCL2, indicating modulation of apoptosis-related factors toward a pro-survival profile. NETs induced AKT phosphorylation in the luminal cell lines and engaged the PI3K\/AKT\/NF-\u03baB signaling axis, consistent with the modulation of downstream apoptotic factors. Inhibition of this pathway or AKT1 knockdown reversed the NET-induced chemoresistant phenotype, restoring chemosensitivity and apoptotic gene expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Collectively, these findings identify heat-labile, NET-associated components as mediators of breast cancer chemoresistance and support targeting NETs or their downstream signaling pathways to improve chemotherapy response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1912140","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:29:54Z","timestamp":1789014594000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neutrophil extracellular traps induce chemoresistance in human breast cancer cells through the PI3K\/AKT\/NF-\u03baB pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Juliana L.","family":"Souza","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Trombose, Inflama\u00e7\u00e3o e C\u00e2ncer, Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro (UFRJ)","place":["Rio de Janeiro, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitor H.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Trombose, Inflama\u00e7\u00e3o e C\u00e2ncer, Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro (UFRJ)","place":["Rio de Janeiro, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Martins-Cardoso","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Trombose, Inflama\u00e7\u00e3o e C\u00e2ncer, Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro (UFRJ)","place":["Rio de Janeiro, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana D. T.","family":"Carneiro","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Sinaliza\u00e7\u00e3o e Biologia Tumoral, Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro (UFRJ)","place":["Rio de Janeiro, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vit\u00f3ria R. D.","family":"Azevedo","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Trombose, Inflama\u00e7\u00e3o e C\u00e2ncer, Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro (UFRJ)","place":["Rio de Janeiro, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Nestal de Moraes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Sinaliza\u00e7\u00e3o e Biologia Tumoral, Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro (UFRJ)","place":["Rio de Janeiro, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robson Q.","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Trombose, Inflama\u00e7\u00e3o e C\u00e2ncer, Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro (UFRJ)","place":["Rio de Janeiro, 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