鸦胆子素A通过Ku70重定位激活cGAS-STING通路增强抗肿瘤免疫的研究

Abstract

DNA-damaging agents combined with agonists of the cGAS-STING pathway can effectively suppress colorectal cancer (CRC) by inducing cancer cell death and eliciting an antitumor immune response. In this study, we demonstrate that the natural compound Bruceine A (BA) inhibits CRC progression through a dual mechanism involving nuclear-to-cytoplasmic translocation of Ku70. Cytoplasmic Ku70 loses its canonical DNA repair function while simultaneously enhancing its interaction with cGAS, leading to increased cGAS oligomerization and elevated levels of double-stranded DNA (dsDNA), both of which amplify cGAS-STING signaling. Furthermore, Bruceine A-mediated Ku70 translocation exacerbates DNA damage accumulation, further enhancing tumor immunogenicity. In the murine CRC model, Bruceine A significantly inhibited tumor growth and enhanced tumor sensitivity to chemotherapy, radiotherapy, and anti-PD-1 treatment. Notably, genetic ablation of STING and CD8 + T cells in mice substantially abolished the antitumor effects of Bruceine A, confirming its reliance on cGAS-STING activation and adaptive immunity. Our findings establish Ku70 as a novel therapeutic target in CRC, where its subcellular redistribution disrupts genomic stability and bridges innate immune activation, synergistically promoting tumor cell death and antitumor immunity. Modulating Ku70 localization thus represents a promising strategy to enhance CRC treatment.