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

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.