{"doi":"10.1172/jci150846","title":"Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues","abstract":"A combination of anti-CTLA-4 plus anti-PD-1/PD-L1 is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAEs). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrating myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFN-γ-dependent mechanism. Targeting the HIF-1α/PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated the cancer immunotherapeutic effects of anti-CTLA-4 therapy, with efficacy comparable to that of anti-CTLA-4 plus anti-PD-1 antibodies. However, while anti-PD-1 exacerbated irAEs triggered by ipilimumab, echinomycin protected mice against irAEs by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1/PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment to achieve safer and more effective immunotherapy.","journal":"Journal of Clinical Investigation","year":2022,"id":233170,"datarank":0.7475409932562506,"base_score":4.983606621708336,"endowment":4.983606621708336,"self_citation_contribution":0.7475409932562506,"citation_network_contribution":0.0,"self_endowment_contribution":0.7475409932562506,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":145,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"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":458366,"name":"Yan Liu","orcid":"0000-0003-4565-4780","position":1,"is_corresponding":false},{"id":845890,"name":"Mingyue Liu","orcid":"0000-0002-4294-0389","position":2,"is_corresponding":false},{"id":418656,"name":"Xuexiang Du","orcid":"0000-0002-7424-7343","position":3,"is_corresponding":false},{"id":419377,"name":"Martin Devenport","orcid":null,"position":4,"is_corresponding":false},{"id":418660,"name":"Pan Zheng","orcid":"0000-0003-2598-3544","position":5,"is_corresponding":false},{"id":105301,"name":"Yang Liu","orcid":"0000-0002-5221-7725","position":6,"is_corresponding":false},{"id":845891,"name":"Yin Wang","orcid":"0000-0002-4749-3768","position":7,"is_corresponding":false},{"id":458365,"name":"Christopher M. Bailey","orcid":"0000-0002-5962-9511","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:21:25.223756Z","pmid":"35239514","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":[]}