Judy Muayad

Background:  Esophageal squamous cell carcinoma (ESCC) is a malignant tumor arising from the squamous epithelium of the esophagus and accounts for most esophageal cancer cases worldwide.¹ Although esophageal adenocarcinoma predominates in many Western countries, ESCC remains a major global cause of cancer mortality, particularly in regions of Asia and Africa.^1,2 Smoking and heavy alcohol consumption are the strongest established risk factors for ESCC and act synergistically to increase cancer risk.^2,3 Despite similar exposures and tumor stages, patient outcomes vary significantly suggesting additional molecular mechanisms influence prognosis. Increasing evidence demonstrates that tobacco and alcohol induced DNA damage, defects in DNA damage repair (DDR) pathways and epigenetic dysregulation contribute to genomic instability and ESCC progression.^1,4

Research Objectives:  This literature review evaluates how smoking and alcohol related DNA damage contributes to defective DDR pathways in ESCC and examines the clinical significance of DDR based molecular subtypes, immune microenvironment alteration, and emerging targeted therapies.

Methods:  An online search in the PubMed database was conducted from 2019 to 2026 using the following keywords: “esophageal squamous cell carcinoma,” “DNA damage repair,” “DDR,” “smoking,” “alcohol,” “DNA methylation,” “genomic instability,” “immune microenvironment,” “and “PARP inhibition.” Primary studies, genomic analyses, transcriptomic studies, and experimental models investigating DDR dysfunction and ESCC prognosis or treatment response were reviewed.

Results:  Environmental carcinogens from tobacco and alcohol exposure promote chronic epithelial injury, DNA damage, and inflammatory signaling within esophageal squamous cells.¹ Experimental mouse models exposed to 4-nitroquinnoline-1-oxide and ethanol demonstrated accelerated ESCC formation, increased DNA damage, and enhanced inflammatory pathway activation compared with either exposure alone.¹ Genomic studies identified early TP53 inactivation, copy number alterations, and defective genomic surveillance as critical events in ECSC development.¹ Epigenetic analysis further demonstrated widespread DNA methylation abnormalities that altered expression of DNA repair genes and correlated with patient prognosis.² Distinct methylation signatures successfully differentiated tumor from normal tissue and may serve as future diagnostic or prognostic biomarkers.² Transcriptomic profiling revealed two major DDR-based molecular subtypes: DDR-active and DDR-silent tumors.⁴ DDR-silent tumors exhibited increased genomic instability, immunosuppressive tumor microenvironments, and significantly poorer survival outcomes compared with DDR-active tumors.^3,4 Differential expression of DDR-related genes was also associated with altered immune cell infiltration and immune signaling pathways, suggesting interactions between genomic instability and tumor immune regulation.³ Additionally, targeting DDR pathways showed therapeutic potential. PART inhibition with olaparib significantly increased radiosensitivity, persistent DNA double-strand breaks, and tumor cell death in resistant esophageal carcinoma cell lines treated with proton irradiation.⁵

Conclusion:  ESCC development is strongly linked to the combined effects of smoking and alcohol induced DNA damage, chronic inflammation, and defective DNA repair pathways. Defective DDR pathways contribute to genomic instability, altered immune responses, and aggressive tumor behavior. Identification of DDR-active and DDR-silent molecular subtypes may help predict patient outcomes and guide treatment decisions. Emerging DDR-targeted treatments, including PARP inhibition, demonstrate promising therapeutic potential for resistant ESCC. Further research is needed to better understand DDR-related tumor biology and develop more effective targeted therapies for ESCC patients.

Works Cited

1. Yuan J, Guo J, Wang Y, et al. Network toxicology reveals collaborative mechanism of 4NQ0 and ethanol in esophageal squamous cell carcinogenesis. Biochemistry and Biophysics Reports. 2025;43:2405- 5808. doi:10.1016/j.bbrep.2025.102187.
2. Xi Y, Lin Y, Guo W. et al. Multi-omic characterization of genome-wide abnormal DNA methylation reveals diagnostic and prognostic markers for esophageal squamous-cell carcinoma. Sig Transduct Target Ther. 2022;7(53). doi:10.1038/s41392-022-00873-8.
3. Guo D, Zhang X, Du X, et al. A novel DNA damage repair gene-related prognostic model for evaluating the prognosis and tumor microenvironment infiltration of esophageal squamous cell carcinoma. BMC Med. Genomics. 2023;16(27). doi:10.1186/s12920-023-01459-1.
4. Zhao N, Zhang Z, Wang Q, et al. DNA damage repair profiling of esophageal squamous cell carcinoma uncovers clinically relevant molecular subtypes with distinct prognoses and therapeutic vulnerabilities. EbioMedicine. 2023. doi:10.1016/j.ebiom.2023.104801.
5. Kageyama SI, Junyan D, Hojo H, et al. PARP inhibitor olaparib sensitizes esophageal carcinoma cells to fractionated proton irradiation. J Radiat Res. 2020;61(2):177-186. doi:10.1093/jrr/rrz088.
6. Jiang W, Zhang B, Xu J. et al. Current status and perspectives of esophageal cancer: a comprehensive review. Cancer Commun (Lond). 2025;45(3):281-331. doi:10.1002/cac2.12645.
7. Ryu DG, Choi CW, Kim SJ, et al. Clinical characteristics and prognosis of esophageal squamous cell carcinoma in patients under 60 years of age. Cancers (Basel). 2025;17(22):3642. doi:10.3390/cancers17223642.
8. Xie Z, Lin J, Li Z, et al. Esophageal cancer trends in the US from 1992 to 2019 with projections to 2044 using SEER data. Sci Rep. 2025;15(1):22423. doi:10.1038/s41598- 025-01674-z