From cigarette to cervix: the transformative pathway of tobacco smoke constituents and their contribution to carcinogenesis

Epidemiological evidence identifies smoking as a dose-dependent risk factor for cervical cancer, particularly in human papillomavirus (HPV)-positive women, elevating progression risk by two- to three-fold. While the interplay between smoking and HPV acquisition remains complex, emerging mechanistic insights reveal a more direct pathway. This review synthesizes current knowledge linking environmental tobacco exposure to cervical carcinogenesis. We detail how tobacco smoke constituents, notably the carcinogens 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and polycyclic aromatic hydrocarbons (PAHs), along with nicotine, enter the body and accumulate in cervical tissue. Crucially, NNK and PAHs undergo metabolic activation into reactive intermediates that form DNA adducts, directly damaging cervical epithelial cells. Nicotine itself is not classified as a human carcinogen but may act as a tumor promoter. This local genotoxic effect, potentially synergistic with HPV oncogenesis, provides biological plausibility for the epidemiological association. The review also highlights the environmental footprint of tobacco and discusses urinary metabolites as biomarkers of carcinogen exposure. In conclusion, smoking contributes to cervical cancer through a defined biological sequence of exposure, distribution, metabolic activation, and DNA damage. Importantly, this direct genotoxic effect is not mutually exclusive but rather synergistic with HPV-driven oncogenesis, offering tangible targets for prevention and mechanistic research.