{"doi":"10.1172/jci190841","title":"4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8+ T cell antitumor response","abstract":"Activating the immune costimulatory receptor 4-1BB (CD137) with agonist antibody binding and crosslinking-inducing agents that elicit 4-1BB intracellular signaling potentiates the antitumor responses of CD8+ T cells. However, the underlying in-depth mechanisms remain to be defined. Here, we show that agonistic 4-1BB treatment of activated CD8+ T cells under continuous antigenic stimulation makes them more metabolically vulnerable to redox perturbation by ablation of intracellular glutathione (GSH) and glutathione peroxidase 4 (GPX4) inhibition. Further, genetic deletion of adenosine A2B receptor (A2BR) induces superior survival and expansion advantage of competent CD8+ T cells with agonistic 4-1BB costimulation, leading to more effective antitumor efficacy of adoptive cell therapy (ACT). Mechanistically, A2BR deletion helps sustain the increased energy and biosynthetic requirements through the GSH/GPX4 axis upon 4-1BB costimulation. A2BR deletion in combination with agonistic 4-1BB costimulation displays a greater ability to promote antitumor CD8+ effector T cell survival and expansion while mitigating T cell exhaustion. Thus, the A2BR pathway plays an important role in metabolic reprogramming with potentiation of the GSH/GPX4 cascade upon agonistic 4-1BB costimulation that allows the fine-tuning of the antitumor responses of CD8+ T cells.","journal":"Journal of Clinical Investigation","year":2025,"id":520859,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"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":855760,"name":"Ping Xie","orcid":"0000-0002-0891-4953","position":1,"is_corresponding":false},{"id":240959,"name":"Siqi Chen","orcid":"0000-0002-9498-3823","position":2,"is_corresponding":false},{"id":1313872,"name":"Guilan Shi","orcid":null,"position":3,"is_corresponding":false},{"id":296412,"name":"Jie Fan","orcid":"0000-0003-3842-2391","position":4,"is_corresponding":false},{"id":181075,"name":"Minghui Zhang","orcid":null,"position":5,"is_corresponding":false},{"id":1390735,"name":"Hui Tang","orcid":"0000-0003-2155-5235","position":6,"is_corresponding":false},{"id":1174588,"name":"A. Zuckerman","orcid":null,"position":7,"is_corresponding":false},{"id":240965,"name":"Deyu Fang","orcid":"0000-0002-4211-2751","position":8,"is_corresponding":false},{"id":254972,"name":"Yong Wan","orcid":"0000-0001-9358-9392","position":9,"is_corresponding":false},{"id":658967,"name":"Timothy M. Kuzel","orcid":"0000-0002-7523-2397","position":10,"is_corresponding":false},{"id":1390736,"name":"Yi Zhang","orcid":"0000-0002-6670-0814","position":11,"is_corresponding":false},{"id":240963,"name":"Bin Zhang","orcid":"0000-0002-6631-7647","position":12,"is_corresponding":false},{"id":479987,"name":"Jihae Ahn","orcid":null,"position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:49:32.958846Z","pmid":"40178905","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":[]}