2026-04-14T07:16:27Zhttps://recercat.cat/oai/request

oai:recercat.cat:2072/4759602025-04-03T10:48:34Zcom_2072_98col_2072_378192

Dual inhibition of TGF-β and PD-L1 : a novel approach to cancer treatment Gulley, James L. Schlom, Jeffrey Barcellos-Hoff, Mary Helen Wang, Xiao-Jing Seoane Suárez, Joan Audhuy, Francois Lan, Yan Dussault, Isabelle Moustakas, Aristidis Universitat Autònoma de Barcelona Immune checkpoint inhibitor PD-L1 TGF-β Tumor microenvironment 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. The TGF-β and PD-L1 signaling pathways have complementary, nonredundant functions in the tumor microenvironment. Dysregulated TGF-β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial-mesenchymal transition, and angiogenesis, while PD-L1 restricts immunosurveillance. We review existing strategies for simultaneous inhibition of these pathways, highlighting dual-targeting agents that may provide colocalized, simultaneous inhibition. 2022 Article https://ddd.uab.cat/record/292962 urn:10.1002/1878-0261.13146 urn:oai:ddd.uab.cat:292962 urn:pmcid:PMC9168966 urn:pmc-uid:9168966 urn:pmid:34854206 urn:oai:pubmedcentral.nih.gov:9168966 urn:articleid:18780261v16p2117 eng Molecular oncology ; Vol. 16 (january 2022), p. 2117-2134 open access Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. https://creativecommons.org/licenses/by/4.0/ application/pdf