Alcohol consumption and cancer progression: Mechanistic insights, immune dysregulation, and public health implications

Alcohol consumption is a modifiable, dose‑dependent risk factor that accelerates cancer initiation, progression, and therapy resistance across breast, liver, colorectal, esophageal, and melanoma cancers. Alcohol metabolism generates acetaldehyde, a genotoxic metabolite that induce DNA damage and impairs repair; drives oxidative stress, hormonal imbalance and promoting a tumor‑supportive microenvironment. These effects are amplified by obesity and insulin resistance, which heighten aggressiveness and blunt treatment response. Alcohol reshapes the tumor immune microenvironment (TIME) and undermines therapies, including immunotherapy. It impairs dendritic cell antigen presentation and co‑stimulation, limits CD4⁺/CD8⁺ priming, and expands immunosuppressive MDSCs and M2‑like TAMs that inhibit cytotoxic T cells and express checkpoint ligands. Concurrent cytokine shifts (TNFα, IL‑6), persistent ROS-NF‑κB signaling, and stromal/vascular remodeling promote immune exclusion and weaken responses to checkpoint blockade, targeted agents, and chemotherapy. Alcohol‑related gut dysbiosis is linked to ICB responsiveness-dampens antitumor immunity. Alcohol increases exosome biogenesis; circulating vesicles enriched in hepatocyte and inflammatory miRNAs (e.g., miR‑122, miR‑192) reprogram immune signaling and metastasis, forming a vesicular axis linking exposure to TIME dysfunction and resistance. Risk is synergistic with tobacco and worsens with aging as detoxification and DNA repair decline. Sex‑specific pharmacokinetics and composition confer vulnerability in women, while socioeconomic barriers delay diagnosis and care. Personalized prevention strategies that incorporate alcohol reduction, smoking cessation, and nutritional support, with emerging biomarkers such as exosomal miRNAs and alcohol‑related metabolites for early detection and risk stratification, are needed to mitigate alcohol‑related carcinogenesis, given the lack of definitive human evidence on alcohol's independent effects on immunotherapy and chemotherapy efficacy.