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This study aims to investigate the impact of nicotine exposure on the regulation of stemness\u2010 and metastasis\u2010related properties via cholinergic receptor nicotinic alpha 9 subunit (CHRNA9) and insulin\u2010like growth factor\u20101 receptor (IGF1R) and to evaluate their therapeutic potential in triple\u2010negative breast cancer (TNBC). We performed Kaplan\u2013Meier survival analysis of public databases and revealed that high expression of CHRNA9, IGF1R signaling molecules, and stemness genes was significantly associated with poor recurrence\u2010free survival (RFS) and distant metastasis\u2010free survival (DMFS) in TNBC samples. Additionally, we examined two patient cohorts to determine the clinical associations between the expression levels of different genes (<jats:italic>n<\/jats:italic>\u2009=\u200967) and proteins (<jats:italic>n<\/jats:italic>\u2009=\u200942) and showed a strong positive correlation between the expression levels of CHRNA9, IGF1R signaling molecules, and stemness markers POU5F1\/NANOG in tumor tissues. We carried out nicotine treatment and knockdown of CHRNA9 and IGF1R in TNBC cells to identify the effects on stemness\u2010related properties <jats:italic>in vitro<\/jats:italic>. Furthermore, primary and secondary metastatic <jats:italic>in vivo<\/jats:italic> animal models were examined using micro\u2010computed tomography (\u03bcCT) screening and <jats:italic>in situ<\/jats:italic> hybridization with a human Alu probe to detect tumor cells. Nicotine was found to upregulate the expression of CHRNA9, POU5F1, and IGF1R, influencing stemness\u2010 and metastasis\u2010related properties. Knockdown of CHRNA9 expression attenuated nicotine\u2010induced stemness\u2010related properties in a TNBC cell model. Furthermore, knockdown of IGF1R expression significantly alleviated nicotine\/CHRNA9\u2010induced stemness features and cancer cell metastasis in cell cultures and lung metastatic mouse models. These results demonstrate that nicotine triggers IGF1R signaling, thereby enhancing stemness\u2010related properties, cell migration, invasion, and tumor metastasis, resulting in a poorer prognosis for patients with TNBC. These findings highlight IGF1R as a promising therapeutic target for reducing stemness and metastasis in TNBC patients exposed to environmental nicotine. \u00a9 2025 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6423","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T10:15:31Z","timestamp":1744884931000},"page":"230-245","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Nicotine\u2010driven enhancement of tumor malignancy in triple\u2010negative breast cancer via additive regulation of <scp>CHRNA9<\/scp> and <scp>IGF1R<\/scp>"],"prefix":"10.1002","volume":"266","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9425-7389","authenticated-orcid":false,"given":"Yung\u2010Che","family":"Kuo","sequence":"first","affiliation":[{"name":"TMU Research Center for Cell Therapy and Regeneration Medicine Taipei Medical University  Taipei 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