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.