This study investigates the epigenetic effects of tobacco and e-cigarette use on DNA methylation (DNAm) in various cell types and tissues. Using computational deconvolution methods, the researchers analyzed DNAm data from over 3,500 buccal/saliva, cervical, and blood samples. They identified 535 smoking-related DNAm loci that clustered into four functional groups based on cell type and anatomic site. These loci were associated with detoxification, growth signaling, and other pathways. Notably, hypermethylation at these sites was observed in buccal epithelial cells of smokers and was also found in e-cigarette users with a limited smoking history. The study highlights the cell type-specific changes in the epigenetic landscape induced by smoking and e-cigarette use, providing insights into their potential carcinogenic mechanisms. The findings suggest that smoking-related DNAm alterations may predict lung cancer development and could be used for noninvasive monitoring.This study investigates the epigenetic effects of tobacco and e-cigarette use on DNA methylation (DNAm) in various cell types and tissues. Using computational deconvolution methods, the researchers analyzed DNAm data from over 3,500 buccal/saliva, cervical, and blood samples. They identified 535 smoking-related DNAm loci that clustered into four functional groups based on cell type and anatomic site. These loci were associated with detoxification, growth signaling, and other pathways. Notably, hypermethylation at these sites was observed in buccal epithelial cells of smokers and was also found in e-cigarette users with a limited smoking history. The study highlights the cell type-specific changes in the epigenetic landscape induced by smoking and e-cigarette use, providing insights into their potential carcinogenic mechanisms. The findings suggest that smoking-related DNAm alterations may predict lung cancer development and could be used for noninvasive monitoring.