Helicobacter pylori is a major human pathogen responsible for chronic gastritis, peptic ulcers, and gastric cancer. Its persistence is facilitated by a complex arsenal of virulence factors, including the CagA oncoprotein, the VacA toxin, adhesins, and the ability to form biofilms. While the roles of individual factors are well-studied, the integrated mechanisms by which they collectively drive carcinogenesis remain a critical knowledge gap. This review integrates evidence showing that CagA delivery and type IV secretion–dependent signals create a transient, infection-driven BRCAness (BRCA1/2 pathway deficiency) state, which is a homologous recombination DNA repair deficiency, promoting error-prone repair and genomic instability. Concurrently, CagA-independent pathways, such as T4SS-mediated ADP-heptose delivery and reactive oxygen species generation, contribute to DNA double-strand breaks. The infection further impairs host defenses by disrupting tumor suppressor pathways such as p53, dysregulating immune signaling of NF-κB and JAK/STAT, which results in immune evasion through arginine depletion and impaired antigen presentation. By elucidating the coordinated interplay among virulence factors, DNA damage response impairment, and immune modulation, this review highlights potential intervention nodes that may help disrupt persistent infection and ultimately reduce the risk of H. pylori -associated gastric cancer.
Rajaei et al. (2026) studied this question.