# Interferon‐Driven Biomarkers and Synergistic Therapy for PRMT5 Inhibition in Triple‐Negative Breast Cancer

## TL;DR

This study identifies interferon signaling as a biomarker for PRMT5 inhibitor response in triple-negative breast cancer and shows that combining PRMT5 inhibition with PARP inhibition enhances treatment effectiveness and immune response.

## Contribution

The study introduces interferon-driven biomarkers and a synergistic therapy combining PRMT5 and PARP inhibition to overcome resistance in TNBC.

## Key findings

- Basal interferon signaling correlates with sensitivity to PRMT5 inhibition in TNBC models.
- Combining PRMT5 inhibition with PARP inhibition activates IFN signaling and sensitizes resistant TNBC cells.
- The combination therapy reshapes the tumor microenvironment and enhances antitumor immunity in pre-clinical models.

## Abstract

Triple‐negative breast cancer (TNBC) exhibits heterogeneous responses to PRMT5 inhibition, posing challenges for therapeutic targeting. Here, using PRMT5 inhibitors, coupled with transcriptomic profiling, basal interferon (IFN) signaling is identified as a biomarker of PRMT5 inhibition sensitivity. Sensitive TNBC models are characterized by elevated DNA damage, which correlated with enriched IFN pathway activity. Pharmacologically inducing DNA damage with the PARP inhibitor Olaparib activated IFN signaling and synergistically sensitized resistant TNBC cells to PRMT5 inhibition. Comprehensive pre‐clinical validation in patient‐derived organoid (PDO) and xenograft (PDX) models demonstrated robust antitumor efficacy of this combination therapy. Moreover, this dual targeting strategy reshaped the tumor microenvironment, enhancing dendritic cell‐CD8+ T cell crosstalk and conferring durable antitumor immunity in vivo. This study establishes IFN‐driven transcriptional signatures as predictive biomarkers for PRMT5 inhibitor response and unveils a rational combination strategy to overcome resistance in TNBC.

Triple‐negative breast cancer exhibits variable sensitivity to PRMT5 inhibition. Basal interferon signaling is identified as a key biomarker of response. PARP inhibition with olaparib induces IFN signaling, sensitizing resistant TNBC cells to PRMT5 inhibitors. Combined treatment remodels the tumor microenvironment and enhances antitumor immunity, offering a precision strategy to overcome therapeutic resistance in TNBC.