Abstract

Immune checkpoint blockade (ICB) shows limited clinical activity in TNBC, largely because immune-cold tumors fail to sustain productive innate and adaptive anti-tumor immunity within an immunosuppressive tumor microenvironment. Here, we identify the transcription factor ARID3A as a tumor-intrinsic regulator of this resistant state. Genetic ablation of ARID3A inflamed the tumor microenvironment, enhanced dendritic-cell activation, increased antigen-specific tetramer-positive and total CD8+ T-cell infiltration with heightened cytotoxic activity, and sensitized otherwise resistant tumors to PD-1 blockade in vivo. Mechanistically, ARID3A restrained endogenous nucleic-acid sensing and downstream type I interferon signaling, predominantly through cGAS-STING with a contributory RIG-I-MAVS component. Through structure-guided drug repurposing, we identified the clinically approved migraine agent rimegepant as an ARID3A-targeting small molecule. Direct binding assays, together with binding-pocket mutations (Y326A and R266A) in matched-expression rescue systems, provided strong genetic evidence for on-target engagement of rimegepant with ARID3A. Rimegepant phenocopied ARID3A loss, reactivated innate immune signaling, and markedly enhanced anti-PD-1 efficacy in murine TNBC models and patient-derived organoids. Collectively, our findings define an actionable ARID3A-IFN axis and support clinical evaluation of rimegepant-based immunotherapy combinations, particularly in ARID3A-high, immune-cold TNBC.