Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer
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 s...
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2025-04-01
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| Online Access: | https://doi.org/10.1186/s12967-025-06258-z |
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| author | Yang Li Pedram Yadollahi Fonma N. Essien Vasanta Putluri Chandra Shekar R. Ambati Karthik Reddy Kami Reddy Abu Hena Mostafa Kamal Nagireddy Putluri Lama M. Abdurrahman Maria E. Ruiz Echartea Keenan J. Ernste Akshar J. Trivedi Jonathan Vazquez-Perez William H. Hudson William K. Decker Rutulkumar Patel Abdullah. A. Osman Farrah Kheradmand Stephen Y. Lai Jeffrey N. Myers Heath D. Skinner Cristian Coarfa Kwangwon Lee Antrix Jain Anna Malovannaya Mitchell J. Frederick Vlad C. Sandulache |
| author_facet | Yang Li Pedram Yadollahi Fonma N. Essien Vasanta Putluri Chandra Shekar R. Ambati Karthik Reddy Kami Reddy Abu Hena Mostafa Kamal Nagireddy Putluri Lama M. Abdurrahman Maria E. Ruiz Echartea Keenan J. Ernste Akshar J. Trivedi Jonathan Vazquez-Perez William H. Hudson William K. Decker Rutulkumar Patel Abdullah. A. Osman Farrah Kheradmand Stephen Y. Lai Jeffrey N. Myers Heath D. Skinner Cristian Coarfa Kwangwon Lee Antrix Jain Anna Malovannaya Mitchell J. Frederick Vlad C. Sandulache |
| author_sort | Yang Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-aa686be31fce4dfc97f22f664eb196db |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-aa686be31fce4dfc97f22f664eb196db2025-08-20T03:07:44ZengBMCJournal of Translational Medicine1479-58762025-04-0123112110.1186/s12967-025-06258-zTobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancerYang Li0Pedram Yadollahi1Fonma N. Essien2Vasanta Putluri3Chandra Shekar R. Ambati4Karthik Reddy Kami Reddy5Abu Hena Mostafa Kamal6Nagireddy Putluri7Lama M. Abdurrahman8Maria E. Ruiz Echartea9Keenan J. Ernste10Akshar J. Trivedi11Jonathan Vazquez-Perez12William H. Hudson13William K. Decker14Rutulkumar Patel15Abdullah. A. Osman16Farrah Kheradmand17Stephen Y. Lai18Jeffrey N. Myers19Heath D. Skinner20Cristian Coarfa21Kwangwon Lee22Antrix Jain23Anna Malovannaya24Mitchell J. Frederick25Vlad C. Sandulache26Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of MedicineBobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of MedicineBobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of MedicineAdvanced Technology Cores, Dan Duncan Cancer Center, Baylor College of MedicineAdvanced Technology Cores, Dan Duncan Cancer Center, Baylor College of MedicineAdvanced Technology Cores, Dan Duncan Cancer Center, Baylor College of MedicineAdvanced Technology Cores, Dan Duncan Cancer Center, Baylor College of MedicineAdvanced Technology Cores, Dan Duncan Cancer Center, Baylor College of MedicineBobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of MedicineDan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Pathology and Immunology, Baylor College of MedicineDepartment of Pathology and Immunology, Baylor College of MedicineDepartment of Pathology and Immunology, Baylor College of MedicineDan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDan L Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Radiation Oncology, Baylor College of MedicineDepartment of Head and Neck Surgery, University of Texas MD Anderson Cancer CenterDepartment of Medicine-Pulmonary, Baylor College of MedicineDepartment of Head and Neck Surgery, University of Texas MD Anderson Cancer CenterDepartment of Head and Neck Surgery, University of Texas MD Anderson Cancer CenterDepartment of Radiation Oncology, University of PittsburghDan L Duncan Comprehensive Cancer Center, Baylor College of MedicineMass Spectrometry Proteomics Core, Baylor College of MedicineMass Spectrometry Proteomics Core, Baylor College of MedicineVerna and Marrs Mclean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineBobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of MedicineBobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of MedicineAbstract 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.https://doi.org/10.1186/s12967-025-06258-zTobaccoNrf2Oxidative stressKeap1GlutathionePDL1 |
| spellingShingle | Yang Li Pedram Yadollahi Fonma N. Essien Vasanta Putluri Chandra Shekar R. Ambati Karthik Reddy Kami Reddy Abu Hena Mostafa Kamal Nagireddy Putluri Lama M. Abdurrahman Maria E. Ruiz Echartea Keenan J. Ernste Akshar J. Trivedi Jonathan Vazquez-Perez William H. Hudson William K. Decker Rutulkumar Patel Abdullah. A. Osman Farrah Kheradmand Stephen Y. Lai Jeffrey N. Myers Heath D. Skinner Cristian Coarfa Kwangwon Lee Antrix Jain Anna Malovannaya Mitchell J. Frederick Vlad C. Sandulache Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer Journal of Translational Medicine Tobacco Nrf2 Oxidative stress Keap1 Glutathione PDL1 |
| title | Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer |
| title_full | Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer |
| title_fullStr | Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer |
| title_full_unstemmed | Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer |
| title_short | Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer |
| title_sort | tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer |
| topic | Tobacco Nrf2 Oxidative stress Keap1 Glutathione PDL1 |
| url | https://doi.org/10.1186/s12967-025-06258-z |
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