Gastric Precancerous Progression Beyond the Correa Cascade: Epithelial State Transitions, Microenvironment Remodeling, and Clonal Evolution

Gastric carcinogenesis is traditionally framed by the Correa cascade, progressing from chronic inflammation and atrophy through intestinal metaplasia (IM) and dysplasia to carcinoma. Although this model remains clinically useful, it does not fully capture the cellular heterogeneity, molecular diversity, and variable outcomes of gastric precancerous progression. Advances in lineage tracing, organoid models, single-cell sequencing, and spatial omics have revealed multiple metaplastic and transitional epithelial states after mucosal injury, while IM itself comprises distinct cellular and molecular programs rather than a uniform precursor state. Concurrent remodeling of immune and stromal compartments, together with metabolic and stress-related changes, may influence the establishment, maintenance, and adaptation of abnormal epithelial states. Epigenetic alterations, somatic mutations, and clonal expansion further shape the selection of epithelial populations across disease stages. Collectively, current evidence supports a nonlinear model in which epithelial state transitions, microenvironmental remodeling, and molecular and clonal evolution jointly shape gastric precancerous progression. However, much of the available evidence remains cross-sectional, and pseudotime trajectories, spatial proximity, and molecular similarity cannot establish true longitudinal evolution or causality in humans. Future studies should combine standardized spatial sampling, longitudinal follow-up within individuals, functional perturbation, and cross-model validation. Candidate molecular and digital pathology biomarkers should also demonstrate incremental predictive value beyond established histologic and endoscopic risk-stratification systems before they can inform individualized surveillance.