{"doi":"10.1101/2025.08.18.670909","title":"BACH2 dosage establishes the hierarchy of stemness and finetunes antitumor immunity in CAR T cells","abstract":"Abstract Self-renewing stem-like T cells promote the efficacy of cancer immunotherapy and are a heterogeneous population with sub-lineages demonstrating different degrees of stemness. At the apex of this hierarchy is long-term (LT) stem-like T cells with the highest capacity of persistence, repopulation and response to immune checkpoint inhibitors (ICI). However, the pathway that establishes the hierarchy of stemness in chimeric antigen receptor (CAR) T cells and its role in antitumor efficacy of CAR T cells are unclear. Here, we demonstrate that LT stem-like differentiation and antitumor immunity of CAR T cells are dose-dependently regulated by BACH2. Pre-infusion LT stem-like CAR T cells showed epigenetic activation of BACH2 and superior antitumor response in mice and humans. After clearing tumor in vivo , LT stem-like T cells emerged as a CAR subset that transcriptionally and epigenetically upregulated BACH2 and downregulated TOX. Loss-of-function experiments revealed an essential role of BACH2 in the antitumor response of CAR T cells and the transcriptional program of LT stem-like CAR T cells. In exhaustion-prone GD2 CAR T cells with high tonic signaling, we showed that quantitative control of BACH2 protein level by a small molecule drug finetuned the degree of stemness and exhaustion in CAR T cells. Chemically inducing temporal BACH2 activation during manufacture of GD2 CAR T cells imprinted greater antitumor immunity against solid tumor after infusion. Together, we show that BACH2 dosage establishes the hierarchy of stem-like CAR T cells and can be temporally and tunably controlled in CAR T cells to optimize differentiation and antitumor immunity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558858,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9426,"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":484320,"name":"Ziang Zhu","orcid":"0009-0008-4231-7213","position":1,"is_corresponding":false},{"id":1459652,"name":"Ying Luo","orcid":"0000-0002-7006-2122","position":2,"is_corresponding":false},{"id":570781,"name":"Safuwra Wizzard","orcid":"0000-0003-1107-8789","position":3,"is_corresponding":false},{"id":1221381,"name":"Jonathan Hoar","orcid":"0009-0004-7584-4141","position":4,"is_corresponding":false},{"id":1221380,"name":"S Shinde","orcid":null,"position":5,"is_corresponding":false},{"id":1025505,"name":"Kiddist Yihunie","orcid":"0000-0002-0863-4863","position":6,"is_corresponding":false},{"id":39928,"name":"Chen Yao","orcid":"0000-0001-6852-5661","position":7,"is_corresponding":false},{"id":623483,"name":"Tuoqi Wu","orcid":"0000-0002-4003-1034","position":8,"is_corresponding":false},{"id":1220840,"name":"Taidou Hu","orcid":"0000-0003-1520-7824","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:30.312295Z","pmid":"40894663","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":[]}