Background: A growing amount of evidence has suggested the clinical importance of stromal and immune cells in the gastric cancer microenvironment. However, reliable prognostic signatures based on assessments of stromal and immune components have not been well-established. This study aimed to develop a stromal-immune score-based gene signature in gastric cancer. Methods: Stromal and immune scores were estimated from transcriptomic profiles of a gastric cancer cohort from TCGA using the ESTIMATE algorithm. A robust partial likelihood-based Cox proportional hazard regression model was applied to select prognostic genes and to construct a stromal-immune score-based gene signature. Two independent datasets from GEO were used for external validation. Results: Favorable overall survivals were found in patients with high stromal score (p = 0.014) and immune score (p = 0.045). Forty-five stromal-immune score-related differentially expressed genes were identified. Using a robust partial likelihood-based Cox proportional hazard regression model, a gene signature containing SOX9, LRRC32, CECR1, and MS4A4A was identified to develop a risk stratification model. Multivariate analysis revealed that the stromal-immune risk score was an independent prognostic factor (p = 0.018). Based on the risk stratification model, the cohort was classified into three groups yielding incremental survival outcomes (log-rank test p = 0.0004). A nomogram integrating the risk stratification model and clinicopathologic factors was developed. Calibration and decision curves showed a better performance and net benefits for the nomogram. Similar findings were validated in two independent cohorts. Conclusion: The stromal-immune score-based gene signature represents a prognosis stratification tool in gastric cancer.

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