{"doi":"10.1016/j.immuni.2025.10.024","title":"IL-9 as a naturally orthogonal cytokine with optimal JAK/STAT signaling for engineered T cell therapy","abstract":"Cytokines and their receptors enable precise tuning of T cell function. Leveraging this biology holds tremendous promise for optimizing antitumor immunity. Arming T cells with a synthetically orthogonal interleukin (IL)-9 receptor (o9R), for instance, permits facile engraftment and potent anti-tumor functions. Exploiting the paucity of wild-type IL-9R expression and the safety of high doses of IL-9, here, we showed that, compared with o9R, T cells engineered with wild-type IL-9R exhibited superior tissue infiltration, stemness, and anti-tumor activity. These qualities were consistent with a stronger Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal, which included canonically IL-12-driven STAT4 in addition to STAT1/3/5. IL-9R T cells were exquisitely sensitive to perturbations of proximal signaling, including structure-guided attenuation, amplification, and rebalancing of JAK/STAT signals. Biased IL-9R mutants showed that STAT1 acts as a rheostat between stem-like and effector states. In summary, we identify IL-9/IL-9R as a naturally orthogonal cytokine-receptor pair with an optimal JAK/STAT signaling profile for engineered T cell therapy.","journal":"Immunity","year":2025,"id":513619,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9432,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":672555,"name":"Sam P. Limsuwannarot","orcid":"0000-0001-8714-7221","position":1,"is_corresponding":false},{"id":401626,"name":"Kayla Kulhanek","orcid":"0000-0001-8831-9806","position":2,"is_corresponding":false},{"id":1375421,"name":"Aastha Pal","orcid":null,"position":3,"is_corresponding":false},{"id":1375422,"name":"Ossama Labiad","orcid":null,"position":4,"is_corresponding":false},{"id":1014595,"name":"Lea Wenting Rysavy","orcid":"0009-0006-2290-6630","position":5,"is_corresponding":false},{"id":954905,"name":"Ada Wong","orcid":"0000-0002-2616-1684","position":6,"is_corresponding":false},{"id":984474,"name":"Leon Su","orcid":"0000-0002-0318-6096","position":7,"is_corresponding":false},{"id":1054474,"name":"Sarah M. Cavender","orcid":null,"position":8,"is_corresponding":false},{"id":1375423,"name":"Johnathon Soro","orcid":null,"position":9,"is_corresponding":false},{"id":795282,"name":"Stefano Testa","orcid":"0000-0001-5632-5021","position":10,"is_corresponding":false},{"id":257944,"name":"Heather Ogana","orcid":"0000-0002-1541-3698","position":11,"is_corresponding":false},{"id":261511,"name":"Deepa Waghray","orcid":null,"position":12,"is_corresponding":false},{"id":1375424,"name":"Pingdong Tao","orcid":null,"position":13,"is_corresponding":false},{"id":260360,"name":"Kevin M. Jude","orcid":"0000-0002-3675-5136","position":14,"is_corresponding":false},{"id":281852,"name":"Christopher S. Seet","orcid":"0000-0002-4821-1400","position":15,"is_corresponding":false},{"id":281853,"name":"Gay M. Crooks","orcid":"0000-0002-2488-8468","position":16,"is_corresponding":false},{"id":252116,"name":"Everett J. Moding","orcid":"0000-0001-7913-5351","position":17,"is_corresponding":false},{"id":218189,"name":"K. Christopher García","orcid":"0000-0001-9273-0278","position":18,"is_corresponding":false},{"id":230467,"name":"Anusha Kalbasi","orcid":"0000-0001-8692-1457","position":19,"is_corresponding":false},{"id":1374816,"name":"Hua Jiang","orcid":"0000-0003-4913-5793","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:48:17.908238Z","pmid":"41274289","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":[]}