Single‐cell RNA sequencing revealed the T‐cell heterogeneity and exhaustion subsets of <i>Helicobacter pylori</i> ‐induced gastritis‐to‐cancer transformation

Abstract Gastric cancer (GC) is the third leading cause of cancer‐related deaths worldwide. Helicobacter pylori ( H. pylori ) infection is a crucial initiative factor for the Correa cascade occurrence of GC. However, the immunological mechanisms of H. pylori ‐induced GC remain incompletely understood, particularly at the single‐cell RNA sequencing (scRNA‐seq) level. We established a scRNA‐seq atlas of gastric tumor, with a focus on T‐cell‐related genes for trajectory analysis, cell–cell communication analysis, and transcription factor regulatory network analysis. The results were validated by immunofluorescence staining of gastric tumors. We collected 63,603 cells from 10 human gastric tissues and identified 20 distinct clusters, annotating 14 cell types based on canonical markers. In‐depth dissection disclosed seven T‐cell subtypes in H. pylori positive gastric tumors. We further revealed two types of exhausted T cells CD4‐C2‐TIGIT (Tex) and CD8‐C3‐PDCD1 (Tex). Among them, CD4‐C2‐TIGIT accounted for the highest proportion in H. pylori positive GC, from which we screened that the gene FYB1 was significantly correlated with prognosis. Immunofluorescence staining verified the localized expression of FYB1 in the T‐cell‐rich areas of H. pylori positive tumors, further substantiating their role in the tumor immune landscape. Moreover, network interaction analysis demonstrated that immune cells, stromal cells, and epithelial cells interact in the tumor microenvironment (TME). Here, we constructs a comprehensive T‐cell atlas of GC, delineating T‐cell heterogeneity and their functional interactions within the H. pylori ‐driven TME. These findings highlight the prognostic potential of FYB1 in tumor immunity and provide new insights into the immunological mechanisms driving GC progression.