Gastric organoids: A promising model for studying “inflammation-cancer” transition in atrophic gastritis

Table 1 Key advances and limitations of gastric organoids in studying inflammation-cancer transition in atrophic gastritis

Research dimension	Key advances	Limitations
Region-specific modeling	(1) Achieved region-specific organoid modeling preserving regional transcriptional signatures[17,22]; and (2) Generated fundic/antral lineages from hiPSCs[16]	(1) Lack of standardized protocols: Phenotypic heterogeneity due to biopsy site variations, medium formulations, and matrix compositions[17]; and (2) Lower efficiency/stability in corpus-derived vs antrum-derived organoids[17,20]
H. pylori infection mechanisms	(1) Revealed CagA/VacA-driven carcinogenesis via Wnt/β-catenin activation, DNA damage, and epigenetic dysregulation[26-28]; and (2) Confirmed persistent DNA damage and cancer risk post-H. pylori eradication[24,32,33]	(1) Failure to recapitulate long-term H. pylori colonization and epithelial-stromal crosstalk[9,10]; and (2) Inadequate integration of immune-stromal microenvironment[79,81]
Premalignant lesion modeling	(1) Successfully modeled IM and SPEM: Revealing CDX2/SOX2-mediated transdifferentiation in IM[34,35] and supporting the role of SPEM as a potential cancer origin; and (2) Demonstrated SPEM–IM-dysplasia sequence[53]	(1) Absence of unified IM modeling protocols, limiting interstudy comparability[12,40]; and (2) Molecular mechanisms of SPEM-to-IM transition require validation[54,55]
TME	(1) Identified CAF-mediated immunosuppression via metabolic reprogramming (lactate) and ECM remodeling[59,61]; and (2) Validated PD-L1 upregulation enabling immune evasion[38,63]	(1) Inability to integrate core TME components (immune cells, stromal crosstalk, microbiota)[9,21]; and (2) Poor simulation of hypoxic niches and mechanical stress[60,66]
Signaling pathway studies	(1) Elucidated synergistic oncogenic roles of MAPK, Wnt/β-catenin, and PI3K/AKT pathways in chronic inflammation[64,67,72]; and (2) Verified targeted interventions (e.g., Rhein inhibiting MAPK/Nrf2)[64]	(1) Difficulty in recreating dynamic cross-talk between multiple pathways[64,69]; and (2) Clinical relevance of pathway activation thresholds needs validation[72,73]
Technical optimization	(1) CRISPR/Cas9 editing simulated TP53/CDH1 mutations accelerating carcinogenesis[24,25]; and (2) PDOs enabled personalized drug screening[97]	(1) MatrigelTM batch variations compromise reproducibility[19,102]; and (2) Phenotypic drift in long-term cultures[86]

H. pylori: Helicobacter pylori; hiPSCs: Human induced pluripotent stem cells; CagA: Cytotoxin-associated protein A; VacA: Vacuolating cytotoxin A; IM: Intestinal metaplasia; SPEM: Spasmolytic polypeptide-expressing metaplasia; CDX2: Caudal-related homeobox transcription factor 2; SOX2: SRY-box transcription factor 2; CAF: Cancer-associated fibroblasts; ECM: Extracellular matrix; PD-L1: Programmed death-ligand 1; MAPK: Mitogen-activated protein kinase; P13K: Phosphoinositide 3-kinase; AKT: Protein kinase B; Nrf2: Nuclear factor erythroid-2-related factor 2; CRISPR/Cas9: Clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats -associated protein 9; CDH1: E-cadherin; PDOs: Patient-derived organoids; TME: Tumor microenvironment.