From Smoke to Stemness: Mechanisms of Cancer Stem Cell Induction by Cigarette Smoke.

Cigarette smoking remains a dominant, preventable driver of cancer morbidity and mortality, and clinical outcomes in smokers remain disproportionately poor even with targeted and immune therapies. Beyond mutagenesis, cigarette smoke (CS) remodels cell state by promoting stem-like programs and enriching cancer stem cells (CSCs), a subpopulation with self-renewal capacity and therapy resistance that drives tumor heterogeneity, metastasis, and treatment failure. CS activates stemness-linked pathways, including Wnt/β-catenin, Notch, Hedgehog/GLI, NF-κB, PI3K/AKT/mTOR, and TGF-β, and remodels the tumor microenvironment to further support CSC properties. While CS effects on lung tissue are well documented, its role in CSC induction at distant organs remains less understood. In this narrative, mechanistically organized review, we examine in vitro, in vivo, and clinical evidence linking CS exposure to CSC induction in primary lung cancer and secondary cancers at distant sites. We propose a unifying framework in which CS acts as a stemness-conditioning exposure that couples oncogenic signaling, epigenetic rewiring, and microenvironmental remodeling to stabilize therapy-evasive CSC states, converging on shared endpoints across tissues via tissue-specific intermediate signaling, and highlight therapeutic vulnerabilities arising from this framework.