Tumoral glucocorticoids induce a phagocytic CD68+/CD163+/C1Q+ macrophage phenotype primed for IFNγ-driven CXCL9 secretion

Glucocorticoids (GCs) play a multifaceted role in modulating immune responses in cancer. Adrenocortical carcinoma (ACC) is a rare endocrine malignancy that produces excessive glucocorticoids in ~ 60%, providing a unique model to study intra-tumoral GC activity. Here, we report that ACC tumors are strongly infiltrated by CD68+/CD163+ 'M2-like' macrophages, independent of cortisol overproduction. In vitro, GC exposure drives the polarization of macrophages towards a C1Q + subtype with enhanced phagocytic activity, mediated by upregulated expression and secretion of the complement component C1q. IFNγ stimulation of C1Q + macrophages significantly enhanced the production and secretion of the T cell chemoattractant CXCL9, surpassing the concentrations produced by classical pro-inflammatory 'M1-like' macrophages. Notably, the presence of intra-tumoral macrophages correlated with increased T cell infiltration, improved patient survival and response to ICI therapy in ACC. Collectively, this study identifies a GC-driven CD68+/CD163+/C1Q + macrophage phenotype with high phagocytic capacity and IFNγ-induced cytokine secretion, suggesting a potential role in T cell recruitment and the enhancement of immunotherapy efficacy in ACC and other solid tumors.