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Glucocorticoids Unleash Immune-dependent Melanoma Control through Inhibition of the GARP/TGFβ Axis

Charles H Earnshaw1,2, Poppy Dunn1, Shih-Chieh Chiang1

  • 1Cancer Inflammation and Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom.

Cancer Discovery
|October 14, 2025
PubMed

Insights

Glucocorticoids (GCs) surprisingly control melanoma tumors by directly reducing GARP on cancer cells, which inhibits TGF-β signaling and enables T cells to kill tumors. This suggests GCs and GARP targeting could improve immunotherapy.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Advanced melanoma patients often resist immune checkpoint blockade, necessitating new therapeutic strategies.
  • Glucocorticoids (GCs) are investigated for their potential anticancer effects in immunotherapy-resistant models.

Purpose of the Study:

  • To investigate the mechanism by which GCs exert anticancer effects in melanoma.
  • To identify potential biomarkers and therapeutic targets for improving melanoma treatment response.

Main Methods:

  • Utilized an immunotherapy-resistant murine melanoma model to test topical medications.
  • Employed genetic ablation of the GC receptor in various cell types to determine the site of action.
  • Analyzed GC receptor and GARP expression in patient melanoma samples.

Main Results:

  • GCs induced cytotoxic T lymphocyte (CTL)-dependent tumor control by directly downregulating glycoprotein A repetitions predominant (GARP) on tumor cells.
  • Downregulation of GARP inhibited TGF-β signaling, thereby enhancing CTL-mediated tumor killing.
  • High GC receptor expression correlated with improved prognosis and reduced TGF-β signaling in patient tumors, while elevated GARP predicted poorer survival.

Conclusions:

  • The GARP/TGF-β axis represents a GC-sensitive, cancer cell-intrinsic mechanism of immune evasion.
  • GCs can enhance anti-tumor immunity by targeting this axis, offering a novel therapeutic approach for melanoma.
  • GARP may serve as a predictive biomarker for immunotherapy response and a target for combination therapies.

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