Integrative multi-omics and experimental validation identify histone acetylation-related genes BCL9L, STX10 and LSM7 as key mediators of PD-1-driven immune evasion and prognosis in non-small cell lung cancer.

[OBJECTIVE] This study explores the impact of histone acetylation-related genes (HARGs) on the PD-1-associated immune microenvironment and prognosis of non-small cell lung cancer (NSCLC) using integrated multi-omics analyses and experimental validation.

[METHODS] The GSE99531 and TCGA-NSCLC datasets were integrated. Differential expression analysis, HARG score calculation (GSVA), and weighted gene co-expression network analysis (WGCNA) were performed. Candidate gene functions were assessed via GO/KEGG enrichment and Mendelian randomization. Experimental validation of BCL9L, STX10, and LSM7 included RT-qPCR, Western blot, CCK-8, colony formation, and mouse model assays.

[RESULTS] A total of 1419 and 6252 differentially expressed genes were identified in the two datasets, respectively. WGCNA selected a module (1560 genes) strongly correlated with HARG scores. Intersection and MR analyses identified 86 causal candidate genes enriched in mitochondrial pathways. Functionally, BCL9L facilitated tumor growth and immune escape, whereas STX10 and LSM7 increased immune infiltration and suppressed tumor progression. Moreover, anti-PD-1 therapy showed synergistic effects with low-risk genes.

[CONCLUSION] Key HARGs (BCL9L, STX10, LSM7) critically influence PD-1-associated immune evasion and prognosis in NSCLC. The established risk model shows significant prognostic value and immune regulatory function, providing new insights for personalized immunotherapy.