What question did this study set out to answer?

This research aims to establish a prognostic signature based on chemokines and uncover the cellular roles in gastric cancer outcomes.

June 19, 2026Open Access

CXCL8 producing macrophages shape gastric cancer outcomes

LZLin ZhangQingdao University HYHanming YuFourth Affiliated Hospital of China Medical University HZHaitao ZhangSouth China Agricultural University

Key Points

This research aims to establish a prognostic signature based on chemokines and uncover the cellular roles in gastric cancer outcomes.
Integrated transcriptomic data from TCGA and GEO cohorts to create a prognostic model with LASSO Cox regression based on six chemokines.
Evaluated associations between risk score, tumor microenvironment characteristics, tumor mutation burden, and drug sensitivity.
Conducted single-cell RNA sequencing to examine the cellular origin and function of CXCL8-producing cells.
Developed a six-chemokine signature that separated patients into distinct risk groups with significant differences in overall survival (OS; p = 0.003) and progression-free survival (PFS; p < 0.001).
Identified the risk score as an independent prognostic factor with good predictive performance (C-index = 0.680).
Found that CXCL8-high macrophages exhibited a pro-tumorigenic phenotype and were key communicators in the tumor microenvironment.

Abstract

BACKGROUND: Gastric cancer (GC) remains a major cause of cancer-related mortality worldwide, highlighting the need for reliable prognostic biomarkers. Although chemokines critically regulate the tumor microenvironment (TME), their integrated prognostic value and mechanistic roles in GC remain unclear. We aimed to develop a chemokine-based prognostic signature and elucidate its underlying cellular basis. METHODS: Transcriptomic data from TCGA and GEO cohorts were integrated to construct and validate a prognostic model using least absolute shrinkage and selection operator (LASSO) Cox regression based on six differentially expressed chemokines. Associations between the risk score and TME characteristics, tumor mutation burden (TMB), and drug sensitivity were evaluated. Single-cell RNA sequencing (scRNA-seq) was performed to determine the cellular origin and functional role of the key chemokine CXCL8. RESULTS: A six-chemokine signature stratified patients into high- and low-risk groups with significantly different overall survival (OS; p = 0.003) and progression-free survival (PFS; p < 0.001). The risk score was an independent prognostic factor, and the corresponding nomogram demonstrated good predictive performance (C-index = 0.680). The high-risk group exhibited elevated TMB and reduced chemosensitivity. scRNA-seq analysis identified macrophages as the principal source of CXCL8. These CXCL8-high macrophages displayed a pro-tumorigenic phenotype and functioned as key communication hubs within the TME, particularly through SPP1 signaling. CONCLUSION: This chemokine-based signature provides clinically relevant prognostic stratification in GC and implicates the CXCL8-macrophage axis as a potential therapeutic target.

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