Targeting ADAR1 Restores Interferon Signaling and Enhances Immunotherapy Response in Multiple Myeloma

Multiple myeloma (MM) remains an incurable hematological malignancy in which tumor-intrinsic immune evasion limits the efficacy of immunotherapy. Here, we identify the RNA editing enzyme ADAR1 as a key regulator of innate immune suppression in MM. Integrative analyses of bulk and single-cell transcriptomic datasets, together with clinical validation, demonstrated that ADAR1 is upregulated in malignant plasma cells and is associated with adverse clinical outcomes and reduced CD8⁺ T-cell infiltration. Mechanistically, ADAR1 knockdown increased the association of endogenous dsRNA with melanoma differentiation-associated protein 5 (MDA5), restoring type I interferon (IFN) signaling, enhancing IFNα production and STAT1 activation, and promoting CD8⁺ T-cell proliferation and cytotoxic function. These effects were largely abolished by MDA5 depletion, establishing a functional ADAR1-MDA5 signaling axis in MM. In vivo, treatment with 8-azaadenosine significantly potentiated the antitumor efficacy of PD-1 blockade, resulting in reduced tumor growth, increased tumor cell apoptosis, elevated IFNα expression, and enhanced CD8⁺ T-cell infiltration. Together, our findings demonstrate that ADAR1-mediated RNA editing enables immune evasion by restricting MDA5-dependent sensing of endogenous dsRNA and highlight the ADAR1-MDA5-type I interferon axis as a promising therapeutic target for improving immunotherapy in multiple myeloma.