Pharmacologic Modulation of ARID3A with Rimegepant Reactivates Type I Interferon Signaling and Sensitizes Triple‐Negative Breast Cancer to PD‐1 Blockade

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.