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

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.