Metabolic-immune interactions in gastric cancer T cells: A single-cell atlas for prognostic biomarker identification

Gastric cancer remains one of the most common causes of cancer-related death worldwide, causing an estimated 660,000 deaths in 2022, and more than 70% of patients are diagnosed at an advanced stage. Although immune checkpoint blockade has transformed cancer immunotherapy, its efficacy in gastric cancer remains limited, with response rates below 20% in unselected cohorts. Tumor progression necessitates the metabolic reprogramming of cancer cells, and metabolic alterations together with immune dysfunction critically drive gastric cancer progression and therapeutic resistance. However, the metabolic landscapes of tumor cells and their interplay with immune components remain underexplored.

Recently, Prof. Junjun Liu and colleagues from Harbin Medical University published a research article, “Metabolic-immune interactions in gastric cancer T cells: A single-cell atlas for prognostic biomarker identification”, in Quantitative Biology, the overall design of which is illustrated in Figure 1. Using single-cell RNA-sequencing of 35,633 cells from 23 gastric cancer tissues (GSE150290), integrated with bulk transcriptomic data from UCSC Xena and two microarray cohorts (GSE26899 and GSE62254), the authors characterized metabolic heterogeneity and T cell trajectories, with key findings validated by RT-qPCR and immunohistochemistry. Of 85 KEGG (Kyoto Encyclopedia of Genes and Genomes database) metabolic pathways, 75 were activated in malignant cells, with the citrate cycle and oxidative phosphorylation driving intratumoral diversity and T cell differentiation; CD8⁺ T cells favored folate biosynthesis and linoleic acid metabolism, CD4⁺ T cells oxidative phosphorylation and purine metabolism, and regulatory T cells the pentose phosphate pathway. A six-gene risk score (RGS1, CXCR4, CTLA4, ARPP19, ZNRF1, ZNF207) stratified patients into high- and low-risk groups with significantly different overall survival, outperformed conventional clinicopathological factors (AUC 0.707–0.803 for 1-, 3-, and 5-year survival), and was confirmed in independent datasets, with immunohistochemistry verifying protein expression of the six genes. Collectively, this study links T cell metabolic reprogramming to gastric cancer immunity and provides a promising prognostic biomarker for risk stratification and personalized management.