TGF-beta: a master immune regulator

Expert Opin Ther Targets. 2020 May;24(5):427-438. doi: 10.1080/14728222.2020.1744568. Epub 2020 Apr 12.


Introduction: Transforming Growth Factor-Beta (TGF-β) is a master regulator of numerous cellular functions including cellular immunity. In cancer, TGF-β can function as a tumor promoter via several mechanisms including immunosuppression. Since the immune checkpoint pathways are co-opted in cancer to induce T cell tolerance, this review posits that TGF-β is a master checkpoint in cancer, whose negative regulatory influence overrides and controls that of other immune checkpoints.Areas Covered: This review examines therapeutic agents that target TGF-β and its signaling pathways for the treatment of cancer which may be classifiable as checkpoint inhibitors in the broadest sense. This concept is supported by the observations that 1) only a subset of patients benefit from current checkpoint inhibitor therapies, 2) the presence of TGF-β in the tumor microenvironment is associated with excluded or cold tumors, and resistance to checkpoint inhibitors, and 3) existing biomarkers such as PD-1, PD-L1, microsatellite instability and tumor mutational burden are inadequate to reliably and adequately identify immuno-responsive patients. By contrast, TGF-β overexpression is a widespread and profoundly negative molecular hallmark in multiple tumor types.Expert Opinion: TGF-β status may serve as a biomarker to predict responsiveness and as a therapeutic target to increase the activity of immunotherapies.

Keywords: Checkpoint Inhibitors; TGF-β; immune regulation; immunotherapy.

Publication types

  • Review

MeSH terms

  • Animals
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immunity, Cellular
  • Immunotherapy / methods
  • Molecular Targeted Therapy*
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Signal Transduction
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / immunology*
  • Tumor Microenvironment


  • Immune Checkpoint Inhibitors
  • Transforming Growth Factor beta