<scp>CD8</scp> ⁺ T Cell Infiltration Elicits Molecular Subtype‐Biased Clinical Outcomes in Gastric Cancer Patients

CD8⁺ T cell infiltration is essential for antitumor immunity across cancers while its clinical significance in gastric cancer (GC) remains unclear. This reflects molecular heterogeneity of GC, as defined by The Cancer Genome Atlas (TCGA) into four subtypes: Epstein-Barr virus (EBV)-positive, microsatellite instability (MSI), chromosomal instability (CIN), and genomically stable (GS), each with distinct immune features. We aimed to characterize distribution, clinical relevance, and immune associations of CD8⁺ T cell infiltration within this molecular framework. TCGA (n = 336) and Zhongshan Hospital (ZSHS, n = 455) cohorts were analyzed. CD8⁺ T cell infiltration and immune features were compared across TCGA subtypes. Prognostic and predictive significance of CD8⁺ T cells was evaluated in ZSHS cohort. CD8⁺ T cell infiltration was elevated in the EBV-positive and MSI subtypes (ZSHS: p = 0.026; TCGA: p < 0.001). In ZSHS cohort, high CD8⁺ T cell infiltration was associated with better overall survival (p = 0.040), particularly in the EBV-positive (p = 0.036) and CIN (p = 0.065) subtypes, but not in MSI (p = 0.440) or GS (p = 0.860). Notably, low CD8⁺ T infiltration predicted superior response to adjuvant chemotherapy in MSI patients (HR = 0.210, p = 0.022). Immune profiling revealed associations of CD8⁺ T cells with antigen presentation in EBV-positive, tertiary lymphoid structure signatures in CIN, and podoplanin+ cells in GS tumors, instead of neoantigen burden in MSI or pan-fibroblast TGFβ response signature in GS. CD8⁺ T cell infiltration demonstrates subtype-specific prognostic and therapeutic significance in GC-beneficial in EBV-positive and CIN tumors, and predictive of chemotherapy response in MSI with low infiltration, which accompanied by divergent immune features, reflecting heterogeneous immunological landscape of GC.