Identification of Immune&Driver Molecular Subtypes Optimizes Immunotherapy Strategies for Gastric Cancer.

Immunotherapy has become a promising treatment for gastric cancer. However, its effectiveness varies significantly across subtypes because of heterogeneous immune microenvironments and genomic alterations. Here, we established Immune&Driver molecular subtypes CS1 and CS2 by systematically integrating multi-omics data for immune-related and driver genes. CS1 was linked to a better prognosis, while CS2 represented a poorer prognostic phenotype. CS1 displayed enhanced genomic instability, marked by higher mutation frequency and chromosomal alterations. In contrast, CS2 exhibited higher immune activity, with a higher density of immune cell infiltration and increased expression of chemokines and immune checkpoint genes. Among FDA-approved anti-cancer agents included in a pan-cancer drug sensitivity prediction framework, CS1 was predicted to be more sensitive to conventional chemotherapeutic agents, whereas CS2 was predicted to be more responsive to immune-related agents. In melanoma datasets, a CS2-like transcriptomic pattern was associated with improved response to anti-PD-1 therapy, with the combination of anti-PD-1 and anti-CTLA-4 showing more favorable response patterns compared to anti-PD-1 monotherapy. Additionally, we developed an immunotherapy response prediction model using PCA-based logistic regression according to the transcriptional expression of CS biomarkers. The model was trained in melanoma immunotherapy cohorts and validated across independent melanoma datasets, and it further achieved a higher AUC in an external gastric cancer cohort treated with anti-PD-1 therapy. Collectively, this study highlights immune and genomic heterogeneity in gastric cancer and provides a hypothesis-generating framework for exploring immunotherapy response.