Pathogenicity of <i>Helicobacter pylori</i> -associated gastric cancer

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide and ranks among the top five most common malignancies. <i>Helicobacter pylori</i> (<i>H. pylori</i>) infection is recognized as the primary risk factor, although gastric carcinogenesis also reflects complex interactions among bacterial virulence factors, host genetics, and the gastric microbiome. <i>H. pylori</i> harbors well-characterized proteins such as CagA, VacA, BabA, and SabA that enable persistent infection and fuel tumor initiation. Recent high-quality evidence from randomized trials and meta-analyses provide strong support that <i>H. pylori</i> eradication therapy substantially reduces cancer risk-even in those with established precancerous lesions such as intestinal metaplasia or dysplasia. Additionally, emerging research indicate that <i>H. pylori</i> may influence the tumor immune microenvironment, such as through altering programmed death ligand 1 expression-which could affect immunotherapy outcomes. This review presents a cohesive and updated perspective on <i>H. pylori</i>-driven GC, summarizing bacterial virulence, host predispositions, microbiome interactions, epigenetic changes like DNA repair gene methylation, and evolving therapeutic implications, all while illuminating current scientific debates and emerging directions.