{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE314nnn/GSE314521/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE314521"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Targeting the ADAR1 p150 isoform to overcome immunotherapy resistance","description":"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 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. Crucially, we delineate the Zα domain as the essential structural determinant for dsRNA editing fidelity. 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 preclinical 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.","dates":{"publication":"2026/04/12"},"accession":"GSE314521","cross_references":{"GSM":["GSM9400256","GSM9400255","GSM9400254","GSM9400253"],"GPL":["24247"],"GSE":["314521"],"taxon":["Mus musculus"]}}