2. Academic Validation
  3. Family with sequence similarity 114 member A1 orchestrates immune evasion in triple-negative breast cancer

Family with sequence similarity 114 member A1 orchestrates immune evasion in triple-negative breast cancer

  • Signal Transduct Target Ther. 2025 Nov 18;10(1):373. doi: 10.1038/s41392-025-02472-9.
Wenhao Zhang # 1,  Yanzhi Gai # 2,  Mengxue Qiao # 1,  Michelle Rowicki 3,  Yong Wei 3,  Xiang Hang 3,  Zhengkai Wei 1,  He Yang 1,  Xifu Ye 2,  Hang Ju 1,  Yi Lu 4,  Yibin Kang 5 6 7,  Minhong Shen 8 9
Affiliations

Affiliations

  • 1 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 2 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 3 Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
  • 4 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China. [email protected].
  • 5 Department of Molecular Biology, Princeton University, Princeton, NJ, USA. [email protected].
  • 6 Cancer Metabolism and Growth Program, The Cancer Institute of New Jersey, New Brunswick, NJ, USA. [email protected].
  • 7 Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, USA. [email protected].
  • 8 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. [email protected].
  • 9 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41249116 DOI: 10.1038/s41392-025-02472-9
Abstract

Immune checkpoint blockade (ICB) therapy, which has revolutionized Cancer treatment, has been approved for the treatment of triple-negative breast Cancer (TNBC). Unfortunately, most patients with TNBC are either not eligible for treatment or exhibit resistance, resulting in limited overall survival benefits. There is an urgent need to elucidate the mechanisms of resistance and enhance therapeutic efficacy. Here, via CRISPR activation (CRISPRa) screening, we identified family with sequence similarity 114 member A1 (FAM114A1) as a key mediator of immune evasion and ICB resistance in TNBC. Mechanistically, FAM114A1 binds p85α to disrupt the p85α/p110α protein complex, thus activating the PI3K/Akt pathway and simultaneously preventing condensate formation of E2F Transcription Factor 4 (E2F4) to promote E2F4-driven Metadherin (MTDH) transcription. Upregulation of these FAM114A1-mediated pathways suppresses tumor antigen presentation and consequently attenuates antitumor immunity in TNBC. Moreover, targeting FAM114A1 improves the therapeutic effectiveness of anti-PD-1 therapy in mouse models, and a FAM114A1-based signature shows strong predictive performance for identifying patients with TNBC who may benefit from ICB. Collectively, our findings not only reveal that FAM114A1 is an immune evasion driver but also highlight it as a promising biomarker and therapeutic target. Our study provides new insights into TNBC immune evasion and outlines a potential avenue to improve the effectiveness of ICB.

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