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.
Pan et al. (Wed,) studied this question.