Targeting the ADAR1 p150 isoform to overcome immunotherapy resistance

The RNA-editing enzyme ADAR1 has emerged as a key regulator of tumor immune evasion, yet therapeutic targeting is challenged by the essential physiological roles of its constitutively expressed p110 isoform. Here, we identify the interferon-inducible p150 isoform and its Zα domain as a precise therapeutic vulnerability.

We demonstrate that ADAR1 p150 is frequently overexpressed in human cancers and correlates with an immunosuppressive tumor microenvironment. Genetic ablation of ADAR1 p150 intrinsically inhibits tumor proliferation and extrinsically triggers a robust type I interferon response and profound remodeling of the tumor immune landscape, converting immunologically "cold" tumors to "hot." Furthermore, we establish that myeloid-specific ADAR1 deletion synergizes with anti-PD-1 therapy by enhancing antigen presentation and fostering a pro-inflammatory microenvironment.