Identification of necrosis-related signature for predicting prognosis and immunotherapy response in gastric cancer

Background: Gastric cancer (GC) is an important malignancy of the digestive system with a high lethal rate. Emerging evidence implicates necrosis-related genes (NRGs) as key regulators of GC progression; however, their specific mechanisms of action within the tumor microenvironment (TME), particularly regarding immune and stromal cell interactions, require further characterization. This study investigates the functional roles and clinical relevance of NRGs in shaping the GC TME. Methods: Utilizing clinical and transcriptomic profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we systematically evaluated 159 necrosis-associated genes in GC. Through differential expression analysis and functional validation, 24 genes demonstrating significant necrosis-related dysregulation were identified. Applying consensus clustering to transcriptomic profiles, we delineated three molecularly distinct necrosis subtypes in GC. These subtypes dynamically regulate distinct pathobiological cascades, functionally link to disease aggressiveness metrics, sculpt tumor immune ecosystems, and stratify patients into differential survival probability groups. Subsequently, we formulated a scoring system termed necrosis score, which was calculated to quantify the different NRG clusters of the individual GC. Results: Integrative analysis revealed a significant negative correlation between necrosis scores and immunogenic biomarkers [programmed death-ligand 1 (PD-L1) expression, tumor mutational burden (TMB), microsatellite instability-high (MSI-H) status], identifying a patient subset with enhanced immunotherapy response rates and superior survival outcomes. The opposite was observed in the high-necrosis score group. Conclusions: Collectively, necrosis subtypes are involved in TME, clinicopathological characteristics, and prognosis. Necrosis score could serve as a potential biomarker for GC and provide a new perspective on developing personalized immune therapeutic strategies for GC patients.