Tobacco-associated carcinogenesis with nicotine-mediated tumor promotion across the gastrointestinal tract: A narrative review.

Abstract

Nicotine exposure remains prevalent through conventional tobacco products and emerging nicotine delivery systems. Although nicotine is not classified as a classical direct genotoxic carcinogen, accumulating evidence suggests that it functions as a tumor-promoting modulator within tobacco-associated carcinogenesis. While individual studies have described organ-specific effects of nicotine within the gastrointestinal (GI) tract, a consolidated synthesis of nicotine-associated mechanisms across GI organ systems has been limited. The aim of this narrative review is to summarize the relevant nicotine-driven pathways and risk factors involved in GI neoplasms. A structured literature search was conducted using PubMed and Google Scholar to identify studies evaluating nicotine-associated carcinogenic mechanisms within the gastrointestinal tract. Four reviewers screened articles after 1993 for relevance to nicotine-mediated gastrointestinal tumorigenesis. Human epidemiological studies, meta-analyses, animal models, and original research were included to capture both clinical associations and molecular signaling pathways. The final search was performed in December 2025. Articles within the literature search describe how nicotine and nicotine-associated signaling influence tumorigenesis throughout the gastrointestinal tract. Across tissues, nicotine activates nicotinic acetylcholine receptors (nAChRs) and downstream signaling cascades that regulate cellular proliferation, apoptosis resistance, angiogenesis, and inflammatory responses. Common pathways include MAPK/ERK, PI3K/AKT, and JAK/STAT signaling, although organ-specific vulnerabilities modify these effects. Tobacco-specific nitrosamines contribute to mutagenesis in oral and pancreatic tissues; YAP/Hippo signaling is implicated in esophageal carcinogenesis; KRAS-associated adenoma-carcinoma progression influences colorectal and pancreatic malignancies; and pro-angiogenic COX-2-mediated pathways support gastric and hepatobiliary tumor growth. Nicotine-associated immune modulation may further facilitate virus-related malignancies in select contexts. Collectively, available data suggest that nicotine acts as a context-dependent tumor promoter across gastrointestinal tissues by amplifying proliferative and inflammatory signaling within established carcinogenic frameworks. By synthesizing molecular and epidemiological findings across GI sites, this review provides a unified framework for understanding nicotine-associated contributions to gastrointestinal tumorigenesis and highlights areas requiring further investigation.