Rethinking gastric carcinogenesis: a multiscale ecological model of risk beyond Helicobacter pylori.

Gastric cancer remains one of the leading causes of cancer mortality worldwide, characterized by marked geographic disparities that cannot be fully explained by the distribution of Helicobacter pylori infection alone. Although H. pylori is recognized as the principal etiological agent, reductionist models centered exclusively on infection prevalence and eradication fail to account for the complex heterogeneity of gastric cancer risk across populations. In this narrative review, we propose a multiscale ecological framework that integrates infectious, host, environmental, microbial, and socioeconomic determinants to reinterpret gastric carcinogenesis as an emergent phenomenon arising from dynamic interactions across biological and geographic scales. Drawing on current epidemiological, molecular, and systems biology evidence, we examine how H. pylori interacts with host genetic susceptibility, epigenetic alterations, microbial community dynamics, dietary exposures, environmental modifiers, and structural social determinants to shape the trajectory of the Correa precancerous cascade. This integrative perspective helps explain key epidemiological paradoxes, including the persistence of high gastric cancer incidence in regions with comparable infection prevalence and the incomplete risk reduction observed after bacterial eradication in advanced mucosal injury. We further highlight the concept of persistent molecular and microenvironmental "carcinogenic memory," whereby epigenetic alterations and dysbiotic microecological states sustain oncogenic potential even after elimination of the infectious agent. By framing gastric carcinogenesis as a complex ecological process rather than a pathogen-driven event, this model bridges mechanistic insights with population-level patterns and provides a conceptual platform for more effective prevention strategies. Ultimately, this framework supports a shift toward integrated approaches that combine early detection, targeted eradication, environmental modification, microbiome-aware strategies, and equitable health policies to reduce the global burden of gastric cancer.