Corticosteroid Influence on Immune Checkpoint Inhibitor Efficacy

Corticosteroids, encompassing both endogenous glucocorticoids and exogenously administered agents, exert profound immunomodulatory effects that can intersect with the mechanisms of immune checkpoint inhibitors (ICIs). By engaging the glucocorticoid receptor (GR), these hormones dampen T-cell activation, reduce pro-inflammatory cytokine production and alter antigen presentation. In the context of cancer immunotherapy, corticosteroids are routinely deployed to manage immune-related adverse events (irAEs), yet their immunosuppressive properties risk attenuation of antitumour efficacy. Emerging evidence also implicates tumour-intrinsic GR signalling and de novo steroidogenesis in T cells as mechanisms of immune evasion. Collectively, these insights underscore a dual-edged nature of corticosteroids: essential for toxicity control but potentially deleterious to ICI-mediated tumour control. Strategies to balance irAE management with preservation of antitumour immunity, including selective GR antagonism and optimised dosing schedules, are therefore of critical importance in clinical practice and translational research.

Research from Nature Portfolio

Recent studies have elucidated a tumour-intrinsic role for GR in modulating immune-checkpoint ligand expression. In pancreatic ductal adenocarcinoma models, GR activation upregulates PD-L1 and represses MHC-I, leading to diminished cytotoxic T-cell infiltration and resistance to ICIs; pharmacological GR inhibition reverses these effects, restoring antigen presentation and antitumour immunity. Complementary work has revealed that tumours can induce de novo steroidogenesis within infiltrating T lymphocytes, driving local immunosuppression. Genetic ablation or pharmacological blockade of the steroidogenic pathway in T cells reinstates effective tumour surveillance and reduces metastatic spread. These findings highlight GR signalling and intratumoural steroid biosynthesis as actionable targets to enhance ICI responsiveness.

Corticosteroid Influence on Immune Checkpoint Inhibitor Efficacy publication trend

The graph below shows the total number of articles in corticosteroid influence on immune checkpoint inhibitor efficacy across all publications each year (not limited to Nature Index journals).

Technical terms

Immune checkpoint inhibitors (ICIs): Monoclonal antibodies that block inhibitory receptors or ligands on immune cells, thereby enhancing antitumour T-cell activity.

Glucocorticoids: Steroid hormones, either endogenous or synthetic, that modulate inflammation and immune responses via the glucocorticoid receptor.

Glucocorticoid receptor (GR): Intracellular receptor that, upon ligand binding, regulates gene transcription to suppress immune activation.

Programmed death-ligand 1 (PD-L1): Immune checkpoint ligand expressed on tumour and immune cells that binds PD-1 on T cells to inhibit their function.

Major histocompatibility complex class I (MHC-I): Cell-surface molecules presenting endogenous peptides to CD8+ T cells, critical for antitumour immunity.

Immune-related adverse events (irAEs): Inflammatory toxicities arising from ICI-induced immune activation that often require immunosuppressive treatment.

Steroidogenesis: The biosynthetic process by which cells produce steroid hormones de novo, including in immune cell subsets within tumours.

References

1. Immunosuppression for immune-related adverse events during checkpoint inhibition: an intricate balance. npj Precision Oncology (2023).
2. Impact of endogenous glucocorticoid on response to immune checkpoint blockade in patients with advanced cancer. Frontiers in Immunology (2023).
3. Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis. Cancers (2020).
4. Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance. Nature Communications (2021).
5. Tumors induce de novo steroid biosynthesis in T cells to evade immunity. Nature Communications (2020).