Single-Cell and Multi-Omics-Based Characterization of Gastric Cancer Identifies TPP1 as a Potential Target for Gastric Cancer Progression and Treatment

Cancer-associated fibroblasts (CAFs) play critical roles in tumor progression and immunosuppression; however, their contribution to the functional classification and personalized treatment of gastric cancer remains poorly defined. This study aimed to identify effective therapeutic targets to facilitate individualized treatment strategies for patients with gastric cancer.

Single-cell and bulk transcriptomic analyses were integrated to characterize gastric cancer fibroblasts. “Seurat”, “Slingshot”, and “CellChat” were used for dimensionality reduction, trajectory inference, and cell–cell communication analyses, respectively. Key metastasis-associated fibroblast modules were identified using High-dimensional weighted gene co-expression network analysis (hdWGCNA) to construct a prognostic model, which was further evaluated for immune infiltration, therapeutic response, and mutational features. The expression and function of the core gene tripeptidyl peptidase 1 (TPP1) were validated through immunoblotting, PCR, and functional assays.

Eight fibroblast subpopulations associated with gastric cancer metastasis exhibited distinct differentiation trajectories and transcriptional heterogeneity. Prognostic analysis indicated that metastasis-associated fibroblasts correlated with poor clinical outcomes. The high-risk subgroup showed marked immunosuppression, resistance to immunotherapy, and reduced mutational burden, with tumor progression–related pathways significantly enriched in this group. In vitro experiments further confirmed that TPP1 knockdown suppressed gastric cancer cell metastasis, invasion, and clonogenic capacity while inducing apoptosis.

This study characterized the heterogeneity of gastric cancer–associated fibroblasts using single-cell transcriptomic analysis and established a prognostic model based on metastasis-related fibroblast markers. The model demonstrated strong predictive performance for patient prognosis, immune landscape, and immunotherapy response. Furthermore, the findings highlighted the pivotal role of TPP1 in gastric cancer progression and its potential as a therapeutic target.