Unraveling the Interplay Between Alcohol, Immunity, and Gastric Cancer: A Genomic Approach.

Gastric cancer poses a major global health burden. Immune evasion is a hallmark of gastric tumorigenesis, yet determinants of anti-tumor immunity and its interactions with cancer development remain unclear. Dietary patterns strongly influence gastric cancer risk, but studies typically examine broad lifestyle factors rather than immune cell populations. We employed Mendelian randomization to investigate potential causal effects of alcohol intake and over 700 immune cell profiles on gastric cancer susceptibility using summary statistics from genome-wide association studies. Multivariable Mendelian randomization and mediation analyses assessed combined effects. SNP annotation characterized immunophenotype-associated genes. Integrative profiling classified gastric cancer subgroups. Mendelian randomization identified immune signatures associated with altered gastric cancer risk, including increased risk from alcohol intake, CD28 on resting Treg and CD62L- HLA DR++ monocyte AC. Multivariable Mendelian randomization provided evidence that higher natural killer cell percentages may lower cancer risk, while naive-mature B cells potentially mediated alcohol's effect. Annotation implicated 104 risk-linked genes in tumorigenesis. Consensus clustering stratified patients by survival dependent on coordinated immunophenotypic programs. Focusing on ACOXL, elevated tumor expression was associated with poorer prognosis. Our study provides genetic and functional evidence linking environmental exposures, immune cell compositions and gastric cancer risk. Findings advance comprehension of disease etiology and establish an integrated immunogenomic framework with implications for precision immunotherapies and disease prevention strategies.