{"doi":"10.1002/hep.32316","title":"Hepatic interferon regulatory factor 8 expression suppresses hepatocellular carcinoma progression and enhances the response to anti–programmed cell death protein‐1 therapy","abstract":"BACKGROUND AND AIMS: Therapeutic blockade of the programmed cell death protein-1 (PD-1) immune checkpoint pathways has resulted in significant reactivation of T cell-mediated antitumor immunity and is a promising clinical anticancer treatment modality in several tumor types, but the durable response rate remains relatively low (15%-20%) in most patients with HCC for unknown reasons. Evidence reveals that the interferon signaling pathway plays a critical role in modulating the efficacy and sensitivity of anti-PD-1 therapy against multiple tumor types, but the mechanisms are unclear. APPROACH AND RESULTS: Using Kaplan-Meier survival analysis based on HCC databases, we found that deceased expression of interferon regulatory factor (IRF) 8 in HCC, among all the nine IRF members that regulate interferon signals, was associated with poor prognosis of patients with HCC. Moreover, gene set enrichment analysis identified the interferon-gamma and PD-1 signaling signatures as the top suppressed pathways in patients with IRF8-low HCC. Contrarily, overexpression of IRF8 in HCC cells significantly enhanced antitumor effects in immune-competent mice, modulating infiltration of tumor-associated macrophages (TAMs) and T cell exhaustion in tumor microenvironment. We further demonstrated that IRF8 regulated recruitment of TAMs by inhibiting the expression of chemokine (C-C motif) ligand 20 (CCL20). Mechanically, IRF8-mediated repression of c-fos transcription resulted in decreased expression of CCL20, rather than directly bound to CCL20 promoter region. Importantly, adeno-associated virus 8-mediated hepatic IRF8 rescue significantly suppressed HCC progression and enhanced the response to anti-PD-1 therapy. CONCLUSIONS: This work identified IRF8 as an important prognostic biomarker in patients with HCC that predicted the response and sensitivity to anti-PD-1 therapy and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.","journal":"Hepatology","year":2022,"id":246911,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9659,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":243275,"name":"Li Yan","orcid":"0000-0002-4792-9998","position":1,"is_corresponding":false},{"id":883744,"name":"Guangjiang Shi","orcid":"0000-0002-2091-0664","position":2,"is_corresponding":false},{"id":883745,"name":"Shijia Du","orcid":"0000-0002-6128-3898","position":3,"is_corresponding":false},{"id":883746,"name":"Xiaobin Wang","orcid":"0000-0003-2428-694X","position":4,"is_corresponding":false},{"id":883747,"name":"Wanli Ye","orcid":"0000-0001-8164-0517","position":5,"is_corresponding":false},{"id":883748,"name":"Zixuan Zhang","orcid":"0000-0002-3894-3704","position":6,"is_corresponding":false},{"id":884210,"name":"Ya Chu","orcid":null,"position":7,"is_corresponding":false},{"id":884211,"name":"Shuqian Ma","orcid":null,"position":8,"is_corresponding":false},{"id":884212,"name":"Dajia Wang","orcid":null,"position":9,"is_corresponding":false},{"id":347447,"name":"Yuan Li","orcid":"0000-0002-4552-5180","position":10,"is_corresponding":false},{"id":749414,"name":"Zhen Chen","orcid":"0000-0003-2447-748X","position":11,"is_corresponding":false},{"id":110422,"name":"Lutz Birnbaumer","orcid":"0000-0002-0775-8661","position":12,"is_corresponding":false},{"id":883749,"name":"Zhuo Wang","orcid":"0000-0002-9482-4486","position":13,"is_corresponding":false},{"id":110421,"name":"Yong Yang","orcid":"0000-0002-2841-8420","position":14,"is_corresponding":false},{"id":749415,"name":"Hongxi Wu","orcid":"0000-0003-3125-0320","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T00:23:48.622830Z","pmid":"34989013","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}