Abstract

Capecitabine has been commonly used for the treatment of early-stage triple-negative breast cancer (TNBC) patients; however, the resistance limits its curative potential. Here, we perform multi-omics data analysis and immunohistochemical (IHC) staining of biological samples from patients in the CBCSG010 clinical trial who were randomized to receive adjuvant docetaxel-anthracycline-based chemotherapy with or without capecitabine. We find that patients with a better prognosis in the capecitabine group exhibited an immune-inflamed microenvironment and upregulation of interferon pathways. Moreover, we identify interferon-related TANK-binding kinase 1-binding protein 1 (TBKBP1) as the key gene involved in capecitabine resistance. We uncover that TBKBP1 promotes capecitabine resistance through impairment of activated immune cells infiltration in vivo. Mechanistically, TBKBP1 negatively regulates type I interferon pathway activated by capecitabine treatment, by promoting autophagy-mediated protein degradation of TANK binding kinase 1 (TBK1). In summary, our study implicates TBKBP1 in mediating capecitabine resistance and may serve as a potential therapeutic target for the treatment of TNBC.