Integrative Transcriptomic Profiling Reveals Histone Variant–Driven Immune Escape in Breast Cancer

Immune evasion, a hallmark of cancer, enables tumors to evade surveillance via camouflage, coercion, and cytoprotection. In breast cancer, we uncovered a transcriptional program mimicking systemic lupus erythematosus (SLE) stress, driving immune escape. Analysis of transcriptomic data (GEO GSE134359, 30 cancer samples) revealed coordinated upregulation of histone variants (e.g., H2AC19, H3C11, H2AX, H4C8, H2BC21, logFC > 2.0, FDR < 0.001) and immune genes (MHC class II, complement, Fc receptors), forming a SLE-related gene module (40 genes, FDR = 7.49 × 10⁻³³). GO/KEGG enrichment underscored antigen processing, immune receptor activity, and chromatin remodeling, suggesting this mimicry induces chronic antigen stimulation. This likely drives CD4⁺ T cell exhaustion and impairs anti-tumor immunity, while complement/Fc receptor upregulation, potentially recruiting immunosuppressive cells sustains inflammation. Unlike passive suppression, this active strategy redefines immune escape. Our findings establish chromatin remodeling, via histone variants like H2A.Z, as an upstream regulator of immune dysfunction, offering new targets to overcome immunotherapy resistance in breast cancer.