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This study explored the anticancer therapeutic potential of an EPS derived from a haloalkaliphilic archaeal strain, which has not been previously isolated from solar salterns on the northwestern Mediterranean Egyptian coast. The selected isolate was identified as <jats:italic>Natrialba chahannaoensis<\/jats:italic> BG8. A Plackett\u2013Burman (PB) fractional factorial design determined NaCl as the only significant variable positively affecting EPS production. The partially purified EPS analytical characterization revealed a carbohydrate content of 75.16\u2009\u00b1\u20092.1%, with Fourier transform infrared (FT-IR) spectroscopy; moreover, GC\u2013MS suggested a heteropolysaccharide nature. For the first time, a neutral red uptake (NRU) assay revealed the anticancer effect of EPS against multiple human cancerous cell lines; A-431 epidermoid cancer (IC<jats:sub>50<\/jats:sub>= 8.8\u00a0mg\/mL), MCF-7 breast cancer (IC<jats:sub>50<\/jats:sub>= 12.7\u00a0mg\/mL), MDA-MB-231 triple-negative breast cancer (TNBC) (IC<jats:sub>50<\/jats:sub>= 9.4\u00a0mg\/mL), and HCT-116 colorectal cancer (IC<jats:sub>50<\/jats:sub>= 10.4\u00a0mg\/mL) cells. Additionally, EPS exhibited previously reported anti-hepatoblastoma activity against HepG-2 cells (IC<jats:sub>50<\/jats:sub>= 21.2\u00a0mg\/mL). The cell cycle analysis results suggested that the antiproliferative effect on MDA-MB-231 cells occurred through S phase arrest. Notably, synergistic interactions between EPS and the anticancer drug paclitaxel (PXL) were recorded in MDA-MB-231 cells via the Chou\u2012Talalay approach. Furthermore, an unpaired Student\u2019s t test disclosed that EPS induced a significant rise in the apoptosis marker caspase-3 (casp-3). This increase was higher than PXL alone and combined with EPS. However, the combined treatment exceeded PXL in significantly reducing MDA-MB-231 cells\u2019 migratory potentials, as evidenced by wound healing and matrix metalloproteinase-9 (MMP-9) determination assays. It also reduced the levels of the oxidative stress marker malondialdehyde (MDA). The EPS of <jats:italic>N. chahannaoensis<\/jats:italic> BG8 displayed a pro-apoptotic action against the TNBC cells MDA-MB-231, surpassing that of PXL. Furthermore, PXL\u2013EPS combination reduced PXL-associated toxicity and increased metastasis control. These findings put EPS as a recommended safe complementary therapy, more effective than PXL monotherapy.<\/jats:p>","DOI":"10.1038\/s41598-025-16243-7","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T20:04:42Z","timestamp":1758657882000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Enhancing the in vitro anticancer efficacy of Paclitaxel against triple-negative breast cancer via an exopolysaccharide from a haloalkaliphilic archaeal strain"],"prefix":"10.1038","volume":"15","author":[{"given":"Afnan","family":"Taghian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona E.M.","family":"Mabrouk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soraya","family":"Sabry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan","family":"Ghozlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma","family":"Elsayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"issue":"1","key":"16243_CR1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.3390\/md18010033","volume":"18","author":"P Corral","year":"2020","unstructured":"Corral, P., Amoozegar, M. 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