Deciphering IFN signaling in gastric cancer: A single-cell and bulk transcriptomic integration reveals CXCR4 as a key immunomodulator and prognostic determinant
- Transl Oncol. 2026 Jun:68:102778. doi: 10.1016/j.tranon.2026.102778.
- 1. Department of Gastrointestinal Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, Fujian Province, China.
- 2. Department of Pharmacy, Jiaocheng District Hospital of Ningde City, Ningde 352100, Fujian Province, China.
- 3. Department of Gastrointestinal Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Branch of Fudan University Shanghai Cancer Center, Fuzhou 350014, Fujian Province, China.
- 4. Department of Gastrointestinal Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Branch of Fudan University Shanghai Cancer Center, Fuzhou 350014, Fujian Province, China.
- 5. Department of Endoscopy Center, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Branch of Fudan University Shanghai Cancer Center, Fuzhou 350014, Fujian, China.
- 6. Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Branch of Fudan University Shanghai Cancer Center, Fuzhou 350014, Fujian Province, China. Electronic address: [email protected].
- 7. Department of Gastrointestinal Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian Branch of Fudan University Shanghai Cancer Center, Fuzhou 350014, Fujian Province, China. Electronic address: [email protected].
- 8. Department of Colorectal Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014 Fujian Province, China. Electronic address: [email protected].
Background: Gastric Cancer (GC), a prevalent solid tumor, features a complex tumor microenvironment (TME) that influences immunotherapy responses. Leveraging single-cell RNA Sequencing (scRNA-seq) and bulk transcriptomics, we dissect the interplay between interferon (IFN) signaling and GC TME to identify actionable targets.
Methods: We analyzed bulk and scRNA-seq datasets. Gene Set Variation Analysis evaluated IFN pathway activity. The Scissor (single-cell identification of subpopulations with bulk sample phenotype correlation) algorithm and weighted gene co-expression network analysis identified survival-associated, IFN-correlated cellular subpopulations. Cell-cell communication within TME was mapped. A multi-gene prognostic signature was constructed and validated. qRT-PCR and Western blot detected marker gene expression. Flow cytometry assessed the proportion of macrophage polarization. CCK-8, Transwell, and scratch assays evaluated cell proliferation and migration.
Results: High IFN activity correlated with improved patient survival. scRNA-seq revealed Macrophages and dendritic cells as primary IFN-activity hubs. Macrophages linked to poor prognosis (Scissor+) exhibited the strongest IFN-γ-driven communication with tumor cells. We established a robust IFN-related prognostic model and pinpointed CXCR4 as a key adverse prognostic biomarker tightly coupled to IFN signaling. Low CXCR4 with high IFN activity defined a favorable prognostic profile. In cell experiments, CXCR4 deficiency in Macrophages activated the IFN signaling pathway. Its overexpression reversed the inhibitory effect of IFN-γ treatment on malignant phenotype of AGS cells.
Conclusions: This study elucidates IFN signaling network within the GC TME at single-cell resolution. We provide a prognostic model and identify CXCR4 as a promising therapeutic target, shedding mechanistic insights for refining immunotherapy strategies in GC.
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