H3K27ac-induced IFITM3 promotes progression of TNBC and resistance to anti-PD-1/PD-L1 therapy via the TNF-α/NF-κB/PD-L1 axis.

Triple-negative breast cancer (TNBC) is highly malignant with limited effective targeted therapies, leading to poor patient outcomes. Although immune checkpoint inhibitors (ICIs) have shown promise in cancer treatment, most patients with TNBC exhibit primary or secondary resistance to ICIs, restricting their clinical use. Interferon-induced transmembrane protein 3 (IFITM3), an interferon-induced protein, is highly overexpressed in various tumors and is associated with immune suppression; however, its role in TNBC progression and immune escape remains unclear. In this study, we investigated IFITM3 expression and its prognostic relevance in TNBC via bioinformatics and clinical validation and explored its functional effects through in vitro and in vivo experiments. IFITM3 was highly expressed in TNBC and correlated with poor prognosis. Its knockdown inhibited proliferation, migration, and invasion, promoted apoptosis, and reduced tumor xenograft growth. Enriched histone H3 lysine 27 acetylation (H3K27ac) in the promoter region led to enhanced IFITM3 transcription. IFITM3 activates the tumor necrosis factor (TNF)-α/nuclear factor kappa B (NF-κB) pathway, leading to upregulated programmed death-ligand 1 (PD-L1) expression, which promotes tumor progression and immune evasion. Blocking the TNF-α/NF-κB pathway reverses the pro-cancer effects of IFITM3. IFITM3 overexpression induced resistance to anti-PD-1 therapy, whereas its knockdown enhanced treatment sensitivity, decreased tumor volume, prolonged survival, increased CD8+ T-cell infiltration, and enhanced tumor apoptosis. In summary, this study revealed that H3K27ac drives IFITM3 transcription in TNBC, activating the TNF-α/NF-κB/PD-L1 axis to promote tumor progression and immunotherapy resistance. Targeting IFITM3 may overcome anti-PD-1 resistance and improve TNBC treatment outcomes.