E2F7 targets S100A2 to suppress CD8⁺T cell activity in lung adenocarcinoma by regulating glutamine metabolism

Malignant cells within the tumor microenvironment have developed numerous strategies to resist the CD8⁺T cell-driven immune response. This study focuses on the mechanism of E2F7/S100A2 axis modulating CD8⁺T cell activity in lung adenocarcinoma (LUAD). Bioinformatics analysis was used to screen for the gene of interest, S100A2, and its regulatory transcription factor E2F7. Expression analysis of S100A2, E2F7, CD8, and PD-L1 at mRNA and protein levels was conducted via qRT-PCR, western blot, or immunohistochemistry. The interaction between S100A2 and E2F7 was validated using dual-luciferase reporter assays and chromatin immunoprecipitation. The interaction between LUAD cells and CD8⁺T cells was explored to understand immune escape mechanisms. Glutamine metabolism (glutamine/glutamate/α-KG/NADPH/GSH levels) and cytotoxicity (LDH/ELISA) were assessed. The impact of the E2F7/S100A2 axis in vivo was examined with LUAD xenograft mouse model. S100A2 was upregulated in LUAD tissues and cells and negatively correlated with CD8⁺T cell infiltration. Enhanced S100A2 expression could modulate glutamine metabolism to dampen the cytotoxic effects of CD8⁺T cells. E2F7 transcriptionally activated S100A2. In animal models, E2F7 knockdown impeded tumorigenesis and encouraged CD8⁺T cell infiltration, but these tumor-suppressive effects were rescued by S100A2 overexpression. This research suggests that E2F7 targets S100A2 to repress the activity of CD8⁺T cells in LUAD by modulating glutamine metabolism, highlighting the potential of targeting the E2F7/S100A2 axis or glutamine metabolic pathways to diminish immune evasion and enhance treatment efficacy in LUAD patients. KEY MESSAGES: S100A2 is upregulated in LUAD and inversely links to CD8⁺T cell infiltration. Enhanced S100A2 expression could manipulate glutamine metabolism. Enhanced S100A2 expression could dampen the cytotoxicity of CD8⁺T cells. S100A2 is transcriptionally activated by E2F7. Targeting E2F7/S100A2 axis may diminish LUAD immune evasion.