Helicobacter pylori-linked gene CFAP73 rewires epithelial programs and shapes the gastric cancer microenvironment

<h4>Background</h4>Helicobacter pylori (HP) infection is the strongest environmental driver of gastric cancer, yet the epithelial programs that are progressively disrupted during infection and are associated with malignant transformation remain unclear.<h4>Methods</h4>Trend-associated genes across HP-infection datasets (GSE60662, GSE60427) were identified using the Jonckheere-Terpstra test and intersected with survival-associated genes in TCGA-STAD. Random-forest modeling, multiple independent validation cohorts, functional analyses, single-cell RNA-seq (GSE249874), ligand-receptor inference, and spatial transcriptomics were integrated to define the biological role and microenvironmental impact of CFAP73.<h4>Results</h4>CFAP73 emerged as the top tumor-protective gene progressively downregulated during HP infection and strongly predictive of favorable survival and cisplatin benefit. CFAP73 expression marked a tumor-suppressive epithelial state characterized by reduced proliferation, EMT inhibition, and activation of p53 and apoptotic pathways. Single-cell analysis showed CFAP73 predominantly in non-malignant epithelial cells, with HP infection driving its loss. CFAP73 + epithelial cells displayed increased LCN2 expression and attenuated oncogenic signaling. Microenvironmentally, CFAP73_high tumors were enriched for effector and Th17 T cells and showed reduced exhausted T cells, Tregs, and pro-tumorigenic CAF states (iCAF, apCAF). Ligand-receptor modeling revealed that CFAP73 + epithelial cells received weaker WNT, TGFβ, and PDGF signals from CAFs but stronger cytotoxic interactions from T cells. Spatial transcriptomics confirmed spatial segregation of CFAP73 + epithelial regions from proliferative, hypoxic, immune-checkpoint-active niches.<h4>Conclusions</h4>CFAP73 is a previously unrecognized epithelial tumor suppressor suppressed early during HP infection. Loss of CFAP73 may contribute to epithelial malignant reprogramming and reshapes fibroblast and T-cell states toward an immunosuppressive, pro-tumor microenvironment. CFAP73 represents a promising biomarker linking HP-driven mucosal injury to gastric cancer initiation, progression, and therapeutic response.