Tumor-intrinsic immune-genetic dynamics identify RNASE1 as an immune-evasion-associated biomarker and predictor of checkpoint blockade response in gastric adenocarcinoma.

Although immune checkpoint blockade (ICB) has changed treatment strategies for gastric adenocarcinoma (STAD), many patients show primary resistance. Tumor-intrinsic transcriptional heterogeneity may contribute to immune escape, but the malignant-cell programs and candidate biomarkers linked to this process remain incompletely defined. Here, we integrated single-cell transcriptomic profiles of 162,116 cells from 35 STAD samples with multiple bulk transcriptomic cohorts to characterize malignant-cell regulatory programs. Non-negative matrix factorization identified meta-program 2 (MP2), a malignant-cell program closely associated with immune-escape signatures. Through integrated co-expression analysis and machine-learning-based prioritization, RNASE1 was identified as an MP2-related candidate biomarker. High RNASE1 expression was associated with poor survival, higher immune and stromal scores, increased immune-checkpoint expression, and enrichment of ICB-response-related transcriptomic signatures. In vitro RNASE1 knockdown reduced STAD cell proliferation, migration, and invasion, supporting a functional contribution to malignant cellular phenotypes. Together, these findings suggest that RNASE1 is an immune-evasion-associated biomarker with potential value for prognosis and ICB-response stratification in STAD, while prospective clinical and in vivo validation remain necessary.