Immunosuppressive microenvironment of TGIF1-overexpressing gastric cancers and its clinical significance

To determine the expression level of TG-interacting factor 1 (TGIF1) in gastric cancer (GC) and its correlation with prognosis, and investigate the characteristics of immune microenvironment of TGIF1-overexpressing GCs and its clinical significance.

Integrated analysis was performed using transcriptomic data from The Cancer Genome Atlas (TCGA), Asian Cancer Research Group (ACRG), and our in-house GC transcriptome database. Immunohistochemistry (IHC) assay was employed to compare TGIF1 expression between GC and normal gastric mucosa tissues. Based on Kaplan-Meier Plotter online database, the correlation between TGIF1 expression and clinical prognosis was evaluated. Transcriptomic data were analyzed to identify functional enrichment features of GC with high TGIF1 expression. The GENIE3 toolkit and STRING database were utilized to predict TGIF1-regulated target genes and protein-protein interaction (PPI) networks, respectively to explore the potential immune-related signaling pathways regulated by TGIF1. Single-cell RNA sequencing (scRNA-seq) was applied to analyze the association between TGIF1 expression and tumor microenvironment (TME) disorder.

Transcriptomic analysis revealed significantly higher TGIF1 expression in GC tissues compared to normal tissues (P<0. 01). Patients with high TGIF1 expression exhibited poorer clinical prognosis (P<0. 05). IHC assay confirmed elevated TGIF1 expression in GC tissues than normal tissues (P<0. 01). GC with high TGIF1 expression was enriched in immune regulatory pathways, including immunosuppressive cytokines such as chemokine C-C motif ligand 20 (CCL20). These tumors displayed an immunosuppressive TME, characterized by abundant immunosuppressive NK cells, mast cells, regulatory T cells (Tregs), myeloid cells, and exhausted CD8⁺ T cells. Cell interaction analysis suggested that TGIF1-overexpressing GC cells may engage with Tregs via the CCL20-CCR6 axis. Co-high expression of signature gene sets from these interacting cells was associated with significantly shorter survival in the patients (P<0. 05).

TGIF1 is highly expressed in GC tissues and may serve as a biomarker for immunosuppressive TME and poor prognosis. TGIF1-overexpressing GC cells may interact with multiple immune cells, particularly Tregs, to induce an immunosuppressive microenvironment.