Work

Inhibition of ATM enhances the immunogenicity of triple-negative breast cancer by promoting MHC-I expression

Year: 2025

Type: article

Abstract: The immunotherapy has achieved some efficacy in triple-negative breast cancer (TNBC), but the benefit population is limited, primarily due to an abnormal immune microenvironment. Thus, it is necessary to explore new molecular targets to enhance the immunogenicity of TNBC cells and improve their responsiveness to immunotherapy. We found that a key component of the DNA repair system, Ataxia telangiectasia mutated (ATM), may function as an immune response inhibitor. In this study, the inverse correlation between ATM and CD8+ T cells and tumor-infiltrating lymphocytes (TILs) was confirmed by immunochemical staining of 191 TNBC specimens. Subsequently, inhibition of ATM increased the expression of major histocompatibility complex I (MHC-I) and enhanced the infiltration and cytotoxic activity of CD8+ T cells by Western blot and flow cytometry analysis. In addition, we further confirmed that the MHC-I upregulation induced by ATM inhibition depends on the activation of the c-Jun/TNF-α/p-STAT1 pathway. Animal studies have shown that ATM deficiency delays tumor growth and sensitizes tumors to PD-1 blockade and radiotherapy. This study reveals a new mechanism by which ATM negatively regulates MHC-I by inhibiting the c-Jun/TNF-α/p-STAT1 pathway in TNBC, and shows an important role in mediating CD8+ T cells infiltration and regulating the “heat” of the immune microenvironment. The combination of ATM inhibitors with radiotherapy and Immune-checkpoint blockade (ICB) therapies may be a new strategy for TNBC treatment.

Source: Cell Death and Disease

DOI: 10.1038/s41419-025-07944-y