The MAD2L1–FOXM1 axis negatively regulates CD4⁺ T cell and macrophages infiltration in lung adenocarcinoma

BACKGROUND: Lung adenocarcinoma (LUAD) exhibits high genetic heterogeneity and an immunosuppressive tumor microenvironment (TME), often characterized by reduced immune cell infiltration. Tumor-intrinsic regulators of cell cycle and genomic stability, such as MAD2L1, may also influence immune evasion, but their mechanistic role in LUAD remains unclear. METHODS: Co-expression profiling was carried out to identify genes positively and negatively associated with MAD2L1 by using Correlation AnalayzeR and was corroborated using ENCORI, GEPIA2 and TIMER2.0 databases. Subsequent prognostic evaluation for all the genes was performed by using KM Plotter. The Spring Viewer transcriptomic database was used to assess the immune cell infiltration patterns correlating with these genes in NSCLC and the association was evaluated using the GSCA and TIMER2.0 databases. Additionally, the expression dynamics across pathological stages was determined by using GSCA. RESULTS: FOXM1 was previously identified as a key upstream regulator of MAD2L1, with co-expression analysis revealing strong positive associations with cell cycle regulators (BIRC5, BUB1B, TTK, CCNA2, DLGAP5) and negative associations with immune-related genes (IL3RA, MPEG1, NCKAP1L, GIMAP8, MS4A14). High MAD2L1 and its positive gene panel correlated with reduced CD4⁺ T cell infiltration, while the negative panel correlated with macrophage-rich TMEs. Stage-wise analysis showed an increase in the positive panel and a decrease in the negative panel from stage I to IV. CONCLUSION: The MAD2L1 axis emerges as a potential driver of immune exclusion in LUAD by suppressing CD4⁺ T cell infiltration, linking tumor proliferation to immune evasion. Targeting this axis may offer a strategy to restore anti-tumor immunity.