{"doi":"10.1073/pnas.2516951122","title":"A TGF-βR/IL-2R immunomodulatory fusion protein transforms immunosuppression into T cell activation to enhance adoptive T cell therapy","abstract":"Adoptive T cell therapies have shown limited efficacy against solid tumors due in part to immunosuppressive cues such as from TGF-β and insufficient survival/proliferative signals within the tumor microenvironment (TME). We engineered chimeric immunomodulatory fusion proteins (IFPs) that convert immunosuppressive TGF-β signals into proliferative/survival Interleukin 2 (IL-2) signals in T cells. Chimeric TGF-βR/IL-2R IFPs were constructed by fusing extracellular domains of the TGF-β receptor chains with intracellular domains of IL-2Rβ and IL-2Rγ to enable TGF-β binding to trigger STAT5 phosphorylation and activate the downstream IL-2 pathway. In human primary CD8 + T cells, select IFP designs robustly induced p-STAT5 upon exposure to TGF-β1, and simultaneously reduced canonical SMAD2/3 signaling. IFP-expressing T cells proliferated and displayed enhanced viability in response to TGF-β1, effectively leveraging TGF-β-rich conditions to outcompete nontransduced cells. Transcriptomic analyses revealed that IFP signaling promoted T cell activation and allowed maintenance of stemness during culture with TGF-β. Functionally, coexpressing IFPs with a mesothelin-specific T cell receptor improved tumor killing and promoted T cell expansion in the presence of TGF-β1, highlighting both neutralization of TGF-β–mediated suppression and enhanced proliferation. TGF-βR/IL-2R IFPs appear promising for reprogramming the signals T cells receive in the TME and improving efficacy of adoptive T cell therapy in solid tumors.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":528915,"datarank":0.16925529105382217,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.004463447753605709,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.004463447753605709,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":2,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"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":1338137,"name":"Ashley Thelen","orcid":"0000-0002-1406-0691","position":1,"is_corresponding":false},{"id":1363209,"name":"Lena V. Wirth","orcid":"0000-0001-7776-2853","position":2,"is_corresponding":false},{"id":1407173,"name":"Cody Jenkins","orcid":"0000-0003-0425-3577","position":3,"is_corresponding":false},{"id":1407645,"name":"Sam R. Mak","orcid":null,"position":4,"is_corresponding":false},{"id":109697,"name":"Daniel Chen","orcid":"0000-0001-6660-6257","position":5,"is_corresponding":false},{"id":18054,"name":"Raphaël Gottardo","orcid":"0000-0002-3867-0232","position":6,"is_corresponding":false},{"id":109737,"name":"Philip D. Greenberg","orcid":"0000-0003-3812-647X","position":7,"is_corresponding":false},{"id":109696,"name":"Yapeng Su","orcid":"0000-0002-6305-8467","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:50:52.565868Z","pmid":"40986340","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":[]}