Immune checkpoint inhibitors (ICIs) in cancer treatment often show limited effectiveness, partly due to poorly understood resistance mechanisms. NR2F6, an orphan nuclear receptor, suppresses anti-tumour cytokines such as IL-2 and IFNγ. High NR2F6 expression levels are linked to current ICI resistance and reduced IFNγ in melanoma. In T cells, NR2F6 limits immune infiltration and activation in tumors. Recent research suggests NR2F6 is expressed in cancer cells and acts directly to suppress anti-tumor immune responses. The current lack of small molecule inhibitors has so far prevented targeting NR2F6 therapeutically.

TES-4207’s interaction with NR2F6 was established using a label-free assay. ChIP experiments in Jurkat cells showed that TES-4207 causes NR2F6 to leave the IL-2 promoter. Antigen-specific T cell activation was measured in vitro. TES-4207’s effects on tumour growth, immune cell infiltration, and the tumor microenvironment were studied in the B16-F1gp100 melanoma mouse model. The impact of combining TES-4207 with αPD-1 therapy was also evaluated in the same model. TES-4207’s activity was compared in wild-type and Nr2f6-null B16-F1gp100 cells created via CRISPR Cas9.

TES-4207 binds NR2F6 with high affinity and detaches it from gene promoters such as IL-2 in Jurkat T cells. It also increases antigen-specific IFNγ production in Pmel1 or OT-I CD8+ T cells ex vivo. In mice, oral TES-4207 significantly slows melanoma growth by promoting increased infiltration of myeloid and lymphoid cells and remodeling the tumor microenvironment. Combining TES-4207 with αPD-1 therapy enhances anti-tumor effects compared to either treatment alone. TES-4207 loses its anti-cancer activity when mice are inoculated with Nr2f6-null cells.

TES-4207 is the first orally available NR2F6 antagonist, capable of converting an immunologically "cold" tumor environment by boosting immune infiltration and slowing tumor progression targeting both immune cells as well as malignant cells. These findings suggest TES-4207 could make patients more responsive to ICI therapy, especially those with poor initial responses. Ongoing studies are further investigating its effects and potential in combination therapies.