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

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 <i>Tsc22d3</i> 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 <i>Tsc22d3</i> expression in myeloid cells, as shown by loss-of-function experiments in myeloid-specific <i>Tsc22d3</i>-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.

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Journal
Proceedings of the National Academy of Sciences
Published
2026-03-04
DOI
https://doi.org/10.1073/pnas.2518983123
Primary Topic
Hormonal Regulation and Hypertension
Type
article
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0.00

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article

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

Flavia Lambertucci, Sabrina Forveille, Ziqi Jin, Vincent Carbonnier et al.
Proceedings of the National Academy of Sciences
Hormonal Regulation and Hypertension
article

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

Flavia Lambertucci, Sabrina Forveille, Ziqi Jin, Vincent Carbonnier, Gautier Stoll, Léa Montégut, Liwei Zhao, Enfu Xue, Zhe Shen, Laurence Zitvogel, Guido Kroemer, Yuting Ma, Eléonore Piard, Hui Pan, Peng Liu, Maria Chiara Maiuri, Isabelle Martins, Oliver Kepp
article en

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 <i>Tsc22d3</i> 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 <i>Tsc22d3</i> expression in myeloid cells, as shown by loss-of-function experiments in myeloid-specific <i>Tsc22d3</i>-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.

Proceedings of the National Academy of SciencesVol. 123(10)
Inserm (FR), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Université Paris Cité (FR), Sichuan University (CN), Université Paris Sciences et Lettres (FR), Université Paris-Saclay (FR), Sorbonne Université (FR), West China Hospital of Sichuan University (CN), Institut d'Imagerie Biomédicale (FR), Centre de Recherche des Cordeliers (FR), Hôpital Européen (FR), Immunité et Cancer (FR), Federico II University Hospital (IT), Suzhou Institute of Systems Medicine (CN), University of Naples Federico II (IT)
Damon Runyon Cancer Research Foundation, Institut National de la Santé et de la Recherche Médicale, National Natural Science Foundation of China, Ligue Contre le Cancer, Sichuan University, Chinese Academy of Medical Sciences, Institut National Du Cancer, Fundo para o Desenvolvimento das Ciências e da Tecnologia, Université Paris-Saclay, Institut Gustave-Roussy, Université de Recherche Paris Sciences et Lettres, Assistance publique-Hôpitaux de Paris, Peking Union Medical College, Sorbonne Université, West China Hospital, Sichuan University, Institute of Cancer Research
Good health and well-being
Openalex Percentile: Top 35%
Hormonal Regulation and Hypertension
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