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

ABSTRACT: Cancer immunotherapy efficacy is often limited by primary and acquired 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 critical 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. Crucially, we delineate the Zα domain as the essential structural determinant for dsRNA editing selectivity. Targeted disruption of this domain alone, without affecting the catalytic deaminase domain, is sufficient to recapitulate the potent antitumor effects of complete ADAR1 ablation, leading to accumulation of immunogenic dsRNA, activation of cytosolic sensors (MDA5/PKR), and potent anti-tumor immunity. Our work provides a compelling rationale for selectively targeting the ADAR1 p150-Zα axis to reverse malignant RNA editing and overcome resistance to immunotherapy, offering a refined strategy with a potentially superior therapeutic index.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE316054 | GEO | 2026/04/12

REPOSITORIES: GEO

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Project description:Sensing of double-stranded RNA (dsRNA) is an important component of innate immunity. Proteins like PKR and MDA5 recognize dsRNA and activate various pathways to fight viral infection. In addition to viral dsRNA, many endogenous RNAs containing double-stranded regions can be misrecognized as immunogenic. The RNA editing enzyme ADAR1, specifically its p150 isoform, has been shown to suppress activation of PKR and MDA5 through its A-to-I editing activity. While the cytoplasmic ADAR1-p150 isoform has been well established within this role, the functions of the nuclear ADAR1-p110 isoform are less understood. To address this knowledge gap, we utilized proximity labeling by APEX2 to identify putative ADAR1-p110 interacting proteins. We identified 110 proteins across three breast cancer cell lines that either interact with p110 or are within close proximity. Many of these proteins have known roles in RNA metabolism. Nine of the identified proteins belong to the DEAD or DEAH box families of RNA helicases, including DHX9. DHX9 is overexpressed in breast cancer, with expression closely correlated with that of p110. By co-immunoprecipitation we confirmed that p110 interacts with DHX9. Knockdown of DHX9 in several triple-negative breast cancer cell lines caused cell death and activation of the dsRNA sensor PKR. In two cell lines that are refractory to knockdown of ADAR1, the combined knockdown of DHX9 and ADAR1 caused a substantial increase in PKR activity, where knockdown of either alone had no effect. Knockdown of DHX9 and ADAR1 caused activation of the type I IFN pathway, RNase L and NF-KB signaling. Activation of these proteins and pathways was not seen with individual knockdown of ADAR1 or DHX9. Activation of PKR following combined knockdown of ADAR1 and DHX9 could be rescued by expression of p110, p150, DHX9, and catalytically inactive DHX9. Additionally PKR activation could be rescued by the dsRBM of DHX9, revealing an important role for dsRBMs in suppressing PKR activation. Together these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways.

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

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