{"doi":"10.1126/sciimmunol.adn9879","title":"Programmable bacteria synergize with PD-1 blockade to overcome cancer cell–intrinsic immune resistance mechanisms","abstract":"Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ–producing bacteria was sufficient to drive systemic tumor antigen–specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3 − CD4 + and CD8 + T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ–producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.","journal":"Science Immunology","year":2024,"id":418740,"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":47,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9451,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1207243,"name":"Zaofeng Yang","orcid":"0000-0003-4861-9729","position":1,"is_corresponding":false},{"id":617613,"name":"Thomas Savage","orcid":"0000-0002-6618-2973","position":2,"is_corresponding":false},{"id":806520,"name":"Rosa L. Vincent","orcid":"0000-0003-0742-8977","position":3,"is_corresponding":false},{"id":1014799,"name":"Kenia de los Santos-Alexis","orcid":"0000-0002-3628-9796","position":4,"is_corresponding":false},{"id":990659,"name":"Alexander Ahn","orcid":"0000-0003-4868-3149","position":5,"is_corresponding":false},{"id":1014798,"name":"Mathieu Rouanne","orcid":"0000-0003-2970-4821","position":6,"is_corresponding":false},{"id":693510,"name":"Dylan L. Mariuzza","orcid":"0000-0002-9369-2514","position":7,"is_corresponding":false},{"id":584126,"name":"Tal Danino","orcid":"0000-0003-2713-7659","position":8,"is_corresponding":false},{"id":617615,"name":"Nicholas Arpaia","orcid":"0000-0002-0657-0528","position":9,"is_corresponding":false},{"id":828769,"name":"Fangda Li","orcid":"0000-0002-4697-3989","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T01:57:09.067930Z","pmid":"39423284","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":[]}