Targeting ADAR1 p150 triggers tumor inhibition and antitumor immunity to overcome immunotherapy resistance

Immunotherapy efficacy is limited by resistance. While ADAR1 regulates tumor immune evasion, targeting it is challenged by the essential role of the constitutive p110 isoform. Here, we identify the interferon-inducible p150 isoform and its Zα domain as critical therapeutic vulnerabilities. ADAR1 p150 is frequently overexpressed in human cancers and correlates with immunosuppressive environments. Genetic ablation of p150 inhibits tumor proliferation and triggers a type I interferon response, converting "cold" tumors to "hot." Myeloid-specific ADAR1 deletion synergizes with anti-PD-1 therapy by enhancing antigen presentation. We establish the Zα domain as the essential determinant for dsRNA editing selectivity. Targeted disruption of this domain alone recapitulates the effects of complete ADAR1 ablation, leading to immunogenic dsRNA accumulation and potent anti-tumor immunity. This work provides a rationale for selectively targeting the ADAR1 p150-Zα axis to reverse malignant RNA editing and overcome immunotherapy resistance with a refined therapeutic index.