Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Agonists as Potential Small Molecule Therapeutics for Cancer Immunotherapy

The recent success of PD-1/PD-L1 antibodies for advanced cancer treatment has led to the conclusion that activating the immune system can be employed to fight cancer. These results also encourage the development of small molecule immunomodulators for cancer immunotherapy. RORγt is a key transcription factor mediating Th17 cell differentiation and IL-17 production, which is able to activate CD8⁺ T cells and elicit antitumor efficacy. Since RORγt agonists have been shown to increase basal activity of RORγt and promote Th17 cell differentiation, development of RORγt agonists could provide a unique approach to cancer immunotherapy. In this review, we summarize RORγt sterol and synthetic agonists, analyze the common ground of their mode of actions, and discuss the potential role of RORγt agonists as small molecule therapeutics for cancer immunotherapy.