{"doi":"10.1002/1878-0261.13146","title":"Dual inhibition of TGF‐β and PD‐L1: a novel approach to cancer treatment","abstract":"Transforming growth factor-β (TGF-β) and programmed death ligand 1 (PD-L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF-β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial-to-mesenchymal transition, and angiogenesis. Meanwhile, PD-L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME. Anti-PD-L1 therapies have been approved for the treatment of various cancers, but TGF-β signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF-β and PD-L1 pathways in cancer, as well as clinical strategies using combination therapies that block these pathways separately or approaches with dual-targeting agents (bispecific and bifunctional immunotherapies) that may block them simultaneously. Currently, the furthest developed dual-targeting agent is bintrafusp alfa. This drug is a first-in-class bifunctional fusion protein that consists of the extracellular domain of the TGF-βRII receptor (a TGF-β 'trap') fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD-L1. Given the immunosuppressive effects of the TGF-β and PD-L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity.","journal":"Molecular Oncology","year":2021,"id":147171,"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":172,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":239943,"name":"Jeffrey Schlom","orcid":"0000-0001-7932-4072","position":1,"is_corresponding":false},{"id":511454,"name":"Mary Helen Barcellos‐Hoff","orcid":"0000-0002-5994-9558","position":2,"is_corresponding":false},{"id":241420,"name":"Xiao‐Jing Wang","orcid":"0000-0001-8695-7361","position":3,"is_corresponding":false},{"id":625955,"name":"Joan Seoane","orcid":"0000-0002-6541-5974","position":4,"is_corresponding":false},{"id":627014,"name":"François Audhuy","orcid":null,"position":5,"is_corresponding":false},{"id":625956,"name":"Yan Lan","orcid":"0000-0002-5850-9737","position":6,"is_corresponding":false},{"id":244141,"name":"Isabelle Dussault","orcid":null,"position":7,"is_corresponding":false},{"id":31071,"name":"Aristidis Moustakas","orcid":"0000-0001-9131-3827","position":8,"is_corresponding":false},{"id":239942,"name":"James L. Gulley","orcid":"0000-0002-6569-2912","position":0,"is_corresponding":true}],"reference_count":112,"raw_metadata":null,"created_at":"2026-07-18T23:42:30.206628Z","pmid":"34854206","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":[]}