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

## TL;DR

This study identifies FAM114A1 as a key protein that helps triple-negative breast cancer evade the immune system and resist treatment, offering a new target for improving therapy.

## Contribution

The study reveals FAM114A1 as a novel driver of immune evasion and resistance to immunotherapy in triple-negative breast cancer.

## Key findings

- FAM114A1 disrupts the p85α/p110α complex and activates the PI3K/AKT pathway to promote immune evasion.
- FAM114A1 prevents E2F4 condensate formation, enhancing MTDH transcription and suppressing tumor antigen presentation.
- Targeting FAM114A1 improves anti-PD-1 therapy effectiveness in mouse models and predicts ICB response in patients.

## 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.