A Novel ROR<i>γ</i>-Selective Agonist Facilitates the Infiltration of Effector T Cells and Innate Immune Cells into Tumor Tissue, Demonstrating Antitumor Efficacy

Retinoic acid receptor-related orphan receptor gamma (RORγ) is a key transcriptional factor that plays a crucial role in the differentiation and activation of Type 17 cells, such as interleukin-17 (IL-17)-producing CD4⁺ T (Th17) cells and CD8⁺ T (Tc17) cells, which are known to boost antitumor responses. Although a RORγ agonist (LYC-55716) has been under clinical evaluation, the precise effects of RORγ agonists on immune cells within tumor environments remain unclear. In our study, we investigated the role of tumor-infiltrating immune cells in the MC38 syngeneic mouse model of colorectal cancer using Compound-34, a novel orally available RORγ-selective agonist we discovered. Our findings revealed that Compound-34 exerts its antitumor efficacy by modulating immune cell activity rather than directly targeting tumor cells. Specifically, Compound-34 increased the infiltration of effector T cells, including Th17 and Tc1 (interferon [IFN]-γ⁺ CD8⁺ T) cells, as well as innate immune cells like natural killer (NK) and natural killer T (NKT) cells, within the MC38 tumor tissue. Following the administration of Compound-34, there was an increase in IFNγ and Granzyme B within the MC38 tumor tissue, accompanied by an increase in the infiltration of cytotoxic immune cells. Moreover, the addition of Th17-derived cytokines to MC38 cells stimulated the release of CXCL10, a chemokine crucial for immune cell recruitment. These results offer valuable insights into the immunomodulatory and therapeutic potential of RORγ agonists in cancer immunotherapy, highlighting their role in enhancing immune cell infiltration and activity within tumors.