2. Academic Validation
  3. Neutralization of acyl-CoA-binding protein attenuates glucocorticoid-mediated suppression of cancer immunosurveillance

Neutralization of acyl-CoA-binding protein attenuates glucocorticoid-mediated suppression of cancer immunosurveillance

  • Proc Natl Acad Sci U S A. 2026 Mar 10;123(10):e2518983123. doi: 10.1073/pnas.2518983123.
Hui Pan # 1 2 3,  Zhe Shen # 1 2 4,  Liwei Zhao 1 2,  Peng Liu 1 2,  Ziqi Jin 5,  Eléonore Piard 6,  Enfu Xue 1 2 4,  Flavia Lambertucci 1,  Gautier Stoll 7,  Vincent Carbonnier 1,  Léa Montégut 1,  Sabrina Forveille 1 2,  Maria Chiara Maiuri 1 8,  Oliver Kepp 1 2,  Laurence Zitvogel 6,  Yuting Ma 5,  Isabelle Martins 1,  Guido Kroemer 1 2 9
Affiliations

Affiliations

  • 1 Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Paris 75006, France.
  • 2 Metabolomics and Cell Biology Platforms, Unité Mixte de Service Analyse Moléculaire, Modélisation et Imagerie de la Maladie Cancéreuse, Gustave Roussy, Villejuif F-94805, France.
  • 3 Department of Hematology/Institute of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 4 Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre 94270, France.
  • 5 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China.
  • 6 Université Paris-Saclay, Gustave Roussy, ClinicoBiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif F-94805, France.
  • 7 Computational Biology and Integrative Genomics of Cancer, INSERM U1331 Computational Oncology, Institut Curie, PSL Research University, Mines Paris Tech, Paris 75248, France.
  • 8 Department of Molecular Medicine and Medical Biotechnologies, University of Napoli Federico II, Naples 80131, Italy.
  • 9 Institut du Cancer Paris Cancer Research for Personalized Medicine, Department of Biology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
  • # Contributed equally.
PMID: 41779791 DOI: 10.1073/pnas.2518983123
Abstract

Glucocorticoids (GCs) are potent immunosuppressive agents that compromise Anticancer immune responses, yet the molecular mediators of this effect remain incompletely understood. Here, we identify the acyl-CoA-binding protein/diazepam-binding inhibitor (ACBP/DBI) as a critical effector of the GC-induced suppression of tumor immunosurveillance and immunotherapy efficacy. Using orthotopic murine models of breast Cancer, non-small cell lung Cancer, and cutaneous fibrosarcoma, we show that corticosterone (CORT) accelerates tumor progression and abrogates therapeutic responses to immunogenic chemotherapy and PD-1 blockade. Genetic ablation or monoclonal antibody (mAb)-mediated neutralization of ACBP/DBI prevents immunosuppression by CORT, restoring both natural and therapy-enhanced antitumor immunity in a T cell-dependent manner. Mechanistically, CORT induces Tsc22d3 expression in dendritic cells, impairs type I interferon signaling, and reduces antigen presentation capacity, which all can be reversed by ACBP/DBI neutralization. The immunosuppressive activity of GCs and the immunostimulatory function of anti-ACBP/DBI mAb converge on Tsc22d3 expression in myeloid cells, as shown by loss-of-function experiments in myeloid-specific Tsc22d3-deficient mice. These findings reveal ACBP/DBI as a central mediator of GC-induced immune evasion and suggest its neutralization as a therapeutic strategy to restore Anticancer immunity during endogenous or iatrogenic GC exposure.

Keywords

Cushing disease; benzodiazepine; corticotherapy; immune checkpoint inhibitor; neuroendocrine signaling.

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