摘要Objective:Gastric cancer(GC)is heterogeneous,and current mismatch repair(MMR)-based classifications incompletely predict response to immune checkpoint inhibitors(ICIs).Methods:RNA sequencing(RNA-seq)and immune infiltration profiles from 189 resected GC were used to derive four refined immune-MMR subtypes(R1-R4)by integrating MMR status,survival,and tumor microenvironment(TME)features.Multi-omics profiling and pathway analysis defined subtype biology.External transcriptomic cohorts and an ICI-treated cohort were classified with Nearest Template Prediction(NTP).Immune response-associated genes were identified from responder vs.non-responder comparisons within the ICI-sensitive subtype and validated by multiplex immunohistochemistry(mIHC).Results:R1 showed the best prognosis and highest immunotherapy response with objective response rate(ORR)54.5%,while R4 had the worst prognosis.R2 represented an immune-unresponsive deficient mismatch repair(dMMR)subset,and R3 captured an immune-active proficient mismatch repair(pMMR)subgroup with moderate therapy sensitivity.Multi-omics integration revealed subtype-specific pathways(e.g.,ECM remodeling in R1,metabolic reprogramming in R2).Reclassification of pMMR tumors based on transcriptional similarity to R1 identified a New R3 subset with enhanced immune features and higher ICI response.Eight immune response-associated genes(e.g.,CXCL10,CXCL11,ELN,GAD1,IL32,MT1E,OR2I1P,SLC3A1)were identified and validated by mIHC for predictive relevance.Conclusions:This immune-based molecular framework refines risk stratification beyond conventional MMR categories,identifies ICI-sensitive subsets among both dMMR and pMMR tumors,and proposes candidate biomarkers for patient selection.