{"doi":"10.1016/j.celrep.2023.112129","title":"TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state","abstract":"TGF-β induces senescence in embryonic tissues. Whether TGF-β in the hypoxic tumor microenvironment (TME) induces senescence in cancer and how the ensuing senescence-associated secretory phenotype (SASP) remodels the cellular TME to influence immune checkpoint inhibitor (ICI) responses are unknown. We show that TGF-β induces a deeper senescent state under hypoxia than under normoxia; deep senescence correlates with the degree of E2F suppression and is marked by multinucleation, reduced reentry into proliferation, and a distinct 14-gene SASP. Suppressing TGF-β signaling in tumors in an immunocompetent mouse lung cancer model abrogates endogenous senescent cells and suppresses the 14-gene SASP and immune infiltration. Untreated human lung cancers with a high 14-gene SASP display immunosuppressive immune infiltration. In a lung cancer clinical trial of ICIs, elevated 14-gene SASP is associated with increased senescence, TGF-β and hypoxia signaling, and poor progression-free survival. Thus, TME-induced senescence may represent a naturally occurring state in cancer, contributing to an immune-suppressive phenotype associated with immune therapy resistance.","journal":"Cell Reports","year":2023,"id":319073,"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":58,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1027666,"name":"Ajinkya Revandkar","orcid":null,"position":1,"is_corresponding":false},{"id":243917,"name":"Taronish D. Dubash","orcid":null,"position":2,"is_corresponding":false},{"id":629945,"name":"Arvind Ravi","orcid":"0000-0003-2461-3533","position":3,"is_corresponding":false},{"id":230831,"name":"Ben S. Wittner","orcid":"0000-0001-5657-9849","position":4,"is_corresponding":false},{"id":267806,"name":"Maoxuan Lin","orcid":"0000-0001-5191-1857","position":5,"is_corresponding":false},{"id":497359,"name":"Robert Morris","orcid":"0000-0003-1615-5915","position":6,"is_corresponding":false},{"id":241919,"name":"Risa Burr","orcid":"0000-0001-6851-2932","position":7,"is_corresponding":false},{"id":241915,"name":"Hongshan Guo","orcid":"0000-0003-2799-2989","position":8,"is_corresponding":false},{"id":1027667,"name":"Karsen Seeger","orcid":null,"position":9,"is_corresponding":false},{"id":230839,"name":"Annamária Szabolcs","orcid":"0000-0003-4951-9914","position":10,"is_corresponding":false},{"id":971770,"name":"Dante Che","orcid":null,"position":11,"is_corresponding":false},{"id":59692,"name":"Linda T. Nieman","orcid":"0000-0002-0141-8308","position":12,"is_corresponding":false},{"id":1058,"name":"Gad Getz","orcid":"0000-0002-0936-0753","position":13,"is_corresponding":false},{"id":43401,"name":"David T. Ting","orcid":"0000-0002-3261-2322","position":14,"is_corresponding":false},{"id":1755,"name":"Michael S. Lawrence","orcid":"0000-0002-1307-459X","position":15,"is_corresponding":false},{"id":311788,"name":"Justin F. Gainor","orcid":"0000-0001-8697-4081","position":16,"is_corresponding":false},{"id":230846,"name":"Daniel A. Haber","orcid":"0000-0003-1378-6551","position":17,"is_corresponding":false},{"id":230847,"name":"Shyamala Maheswaran","orcid":"0000-0002-9356-1709","position":18,"is_corresponding":false},{"id":564377,"name":"Satoru Matsuda","orcid":"0000-0001-7538-6962","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T01:07:06.454099Z","pmid":"36821441","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":[]}