Faculty, Staff and Student Publications
Publication Date
4-5-2025
Journal
Journal of Translational Medicine
Abstract
Background: Exposomes are critical drivers of carcinogenesis. However, how they modulate tumor behavior remains unclear. Extensive clinical data show cigarette smoke to be a key exposome that promotes aggressive tumors, higher rates of metastasis, reduced response to chemoradiotherapy, and suppressed anti-tumor immunity. We sought to determine whether smoke itself can modulate aggressive tumor behavior in head and neck squamous cell carcinoma (HNSCC) through reprogramming of the cellular reductive state.
Methods: Using established human and murine HNSCC cell lines and syngeneic mouse models, we utilized conventional western blotting, steady state and flux metabolomics, RNA sequencing, quantitative proteomics and flow cytometry to analyze the impact of smoke exposure on HNSCC tumor biology and anti-tumor immunity.
Results: Cigarette smoke persistently activated Nrf2 target genes essential for maintenance of the cellular reductive state and survival under conditions of increased oxidative stress in HNSCC regardless of human papillomavirus (HPV) association. In contrast to e-cigarette vapor, conventional cigarette smoke mobilizes cellular metabolism toward oxidative stress adaptation, resulting in development of cross-resistance to cisplatin. In parallel, smoke exposure modulates expression of PDL1 and the secretory phenotype of HNSCC cells resulting in an altered tumor immune microenvironment (TIME) in syngeneic mouse models and downregulated expression of antigen presentation and costimulatory genes in myeloid cells.
Conclusion: The cigarette smoke exposome is a potent activator of the Nrf2 pathway and appears to be the primary trigger for a tripartite phenotype of aggressive HNSCC consisting of: (1) reduced chemotherapy sensitivity, (2) enhanced metastatic potential and (3) suppressed anti-tumor immunity.
Keywords
Head and Neck Neoplasms, Animals, Humans, Oxidative Stress, Cell Line, Tumor, Mice, Squamous Cell Carcinoma of Head and Neck, Immunity, NF-E2-Related Factor 2, Gene Expression Regulation, Neoplastic, Smoke, Tobacco, Nrf2, Oxidative stress, Keap1, Glutathione, PDL1
DOI
10.1186/s12967-025-06258-z
PMID
40188338
PMCID
PMC11971752
PubMedCentral® Posted Date
4-5-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons, Otolaryngology Commons, Translational Medical Research Commons