IFNγ induces epigenetic remodeling of ICAM1 to sensitize triple-negative breast cancer to Vδ2 T cell cytotoxicity

Triple-negative breast cancer (TNBC) remains difficult to treat, and the tumor-intrinsic determinants of response to γδ T cell immunotherapy are poorly defined. Here, we investigated the antitumor role of Vδ2 γδ T cells in breast cancer and explored strategies to enhance their efficacy. Using bioinformatic analyses, biophysical profiling, in vitro cytotoxicity assays, and in vivo adoptive transfer models, we found that tumor-infiltrating γδ T cells were associated with improved prognosis, while breast cancer subtypes showed heterogeneous sensitivity to Vδ2 T cell killing that correlated with ICAM1 expression. In vivo, ICAM1-high tumors were markedly more responsive to Vδ2 T cell therapy, whereas ICAM1 knockout abolished therapeutic benefit, demonstrating that tumor ICAM1 is required for effective Vδ2 T cell–mediated control. Mechanistically, Vδ2 T cell-derived IFNγ was associated with enhanced tumor glycolysis, increased acetyl-CoA levels, and increased histone H3K acetylation at the ICAM1 locus, supporting a contribution of metabolic-epigenetic regulation to ICAM1 upregulation and tumor sensitization. IFNγ also induced PD-L1, suggesting adaptive immune resistance. Accordingly, IFNγ priming combined with PD-1 blockade and Vδ2 T cell transfer significantly improved antitumor efficacy in vivo. These findings identify ICAM1 as a biomarker and therapeutic sensitization target for γδ T cell-based immunotherapy in TNBC.