2. Academic Validation
  3. TBKBP1 induces capecitabine resistance through negative regulation of type I interferon pathway in triple-negative breast cancer

TBKBP1 induces capecitabine resistance through negative regulation of type I interferon pathway in triple-negative breast cancer

  • Oncogene. 2026 Feb;45(6):703-714. doi: 10.1038/s41388-025-03598-4.
Wen-Ya Wu # 1 2,  Yun-Song Yang # 1 2,  Lisa Andriani 1 2,  Yi-Fan Xie 1 2,  Gen-Hong Di 3 4,  Zhi-Ming Shao 5 6,  Jun-Jie Li 7 8
Affiliations

Affiliations

  • 1 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, Key Laboratory of Breast Cancer in Shanghai, Shanghai, People's Republic of China.
  • 3 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China. [email protected].
  • 4 Department of Oncology, Shanghai Medical College, Fudan University, Key Laboratory of Breast Cancer in Shanghai, Shanghai, People's Republic of China. [email protected].
  • 5 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China. [email protected].
  • 6 Department of Oncology, Shanghai Medical College, Fudan University, Key Laboratory of Breast Cancer in Shanghai, Shanghai, People's Republic of China. [email protected].
  • 7 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China. [email protected].
  • 8 Department of Oncology, Shanghai Medical College, Fudan University, Key Laboratory of Breast Cancer in Shanghai, Shanghai, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 41606294 DOI: 10.1038/s41388-025-03598-4
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.

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