Activation of cuproptosis amplifies immunogenic cell death for anti-tumor immunotherapy in gastric cancer

Cuproptosis is a novel form of cell death mediated by protein lipid acylation and highly related to mitochondrial metabolism. Copper directly binds to the fatty acylation component of the tricarboxylic acid (TCA) cycle, resulting in toxic protein stress and ultimately leading to cell death. Immunogenic cell death (ICD) can effectively enhance tumor immunogenicity and induce systemic anti-tumor immunity. However, the relationship between copper-induced cell death and immunogenicity in gastric cancer remains unclear. We utilized the R package to conduct KEGG and GO analysis on differentially expressed genes (DEGs) associated with crucial copper-induced cell death genes in gastric cancer, confirming the potential of copper-induced cell death genes to enhance anti-tumor immunity. Examination of online databases revealed a significant reduction in the expression of key genes related to copper-induced cell death in gastric cancer tissues compared to normal gastric tissues. The expression of cuproptosis-related genes exhibited a negative correlation with the abundance of Treg and MDSC cells, while showing a positive correlation with the expression of ICD-related genes. Furthermore, we validated the impact of key copper-induced cell death genes on subcutaneous tumor growth and ICD in vivo. Tumor tissues with high FDX1 expression demonstrated increased levels of CD8 ⁺ T cells, perforin 1 (PRF1), high mobility group box 1 (HMGB1), and Cu ²⁺ . In conclusion, the activated copper-dependent death-key genes ultimately facilitate immunogenic cell death in gastric cancer, thereby augmenting the anti-tumor immune response in gastric cancer.