Endogenous glucocorticoids and glucocorticoid receptor signaling: Dual regulators of PD-1/PD-L1 immunotherapy efficacy in the tumor microenvironment.

Immunotherapy targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has significantly improved outcomes for various cancers, yet the emergence of resistance remains a major challenge. This review focuses on the dual role of endogenous glucocorticoids (GCs) and their receptor (GR) within the tumor microenvironment (TME), systematically elucidating the mechanisms by which they regulate responses to PD-1/PD-L1 therapy via the hypothalamic-pituitary-adrenal (HPA) axis, local synthesis and metabolism, and heterogeneity of GR signaling. We elaborate on the regulatory effects of the GC/GR signaling pathway on immune cells (such as cluster of differentiation 8 positive [CD8 + ] T cells, regulatory T cells [Tregs], dendritic cells, natural killer [NK] cells, and macrophages), and highlight the impact of GCs on PD-L1 expression, cytokine secretion, and the immunosuppressive microenvironment. This review also explores the controversial role of exogenous GCs in managing immune-related adverse events (irAEs) and their potential impact on therapeutic efficacy. The development of tissue-selective GR modulators holds promise for balancing immunosuppression while enhancing anti-tumor activity. A deeper understanding of the role of endogenous GCs in cancer immunotherapy is crucial for optimizing therapeutic strategies, overcoming resistance, and finally achieving precision in cancer immunotherapy.