Target NR2F6: Immune Checkpoint and Regulate T Cell Differentiation and Exhaustion

NR2F6 is an immune checkpoint target found in melanoma and is a member of the nuclear hormone receptors (NRs) family. Creative Biolabs introduces the NR2F6 target, which is thought to be a central checkpoint for immunosuppression of inflammatory and antitumor responses in the central nervous system.

NRs Family and NR2F6

NRs control regulatory pathways for proliferation, metabolism, specialized cell function and immune cell activity in normal cells. In hormone-associated tumors, NRs are dysregulated and serve to regulate tumor cell communication with the tumor microenvironment (TME).

NR signaling pathways in cancer biology. (Zhao, Linjie, et al., 2019)Fig. 1 NR signaling pathways in cancer biology.1

Different NRs have different roles in tumors. For example, activation of hepatic X receptors induces apolipoprotein E expression within the melanoma ecotope to attenuate MDSC activity and thus inhibit metastasis more effectively, whereas tumor-derived retinoic acid induces differentiation of monocytes into immunosuppressive tumor-associated macrophages (TAMs) to inhibit ICT effects.

NR2F6, also known as Ear-2 or COUP-TFIII, is a member of the NR2F subfamily and is structurally related to the NR2F1 and NR2F2 proteins. NR2F6 has been implicated as a central checkpoint for immunosuppression of inflammatory and antitumor responses in the central nervous system.

The expression of NR2F6 is significantly higher than that in non-tumor tissues in a variety of human tumors, including ovarian cancer, cervical cancer, lymphoma, leukemia, gastric adenocarcinoma, endometrial carcinoma, uroepithelial carcinoma of the bladder, invasive carcinoma tissues of the breast, and colorectal cancer.

Regulatory Mechanisms of NR2F6

  • Lymphocyte-expressed NR2F6 acts as a key regulator during T lymphocyte activation, effectively antagonizing antigen receptor-induced cytokine responses in vitro and in vivo. DNA binding of NR2F6 is under direct control of TCR-induced PKC signaling, which is known to positively modulate CD3 T cell activation thresholds. NR2F6 also plays an important role for Th17 cell lineage.
  • In immune cells, NR2F6 is thought to fine-tune adaptive immunity and suppress the transcriptional capacity of genes encoding cytokines such as IL-2, IFN-γ, IL-17 and IL-21. Endogenous NR2F6 expression in tumor cells controls T cell infiltration.
  • In a genetic mouse model with NR2F6 ablation, NR2F6 caused enhanced activity of tumor-infiltrating effector T cells, resulting in the secretion of more IFN-γ and IL-2, as well as enhanced CD8 T-cell memory, which exhibited accelerated development of inflammation, presentation of an autoimmune phenotype, and attenuated tumor growth, demonstrating a better effect than immune checkpoint PD-1 treatment alone.

Advancements in NR2F6 Targeted Therapies

The complex involvement of NR2F6 in immune regulation and T cell differentiation depletion makes it a promising therapeutic target. In the context of autoimmune diseases, where aberrant immune activation leads to tissue damage, targeting NR2F6 may provide a way to restore immune homeostasis without compromising the overall integrity of the immune system.

In addition, the emerging role of NR2F6 in T cell depletion opens up new avenues for cancer immunotherapy. Strategies aimed at inhibiting NR2F6 may revitalize depleted T cells in the tumor microenvironment, thereby enhancing the efficacy of existing immunotherapeutic approaches.

  • High-throughput screening and structure-based drug design have identified candidate compounds that exhibit promising NR2F6 inhibitory activity. Several small molecule inhibitors have shown efficacy in preclinical models, attenuating NR2F6-mediated transcriptional repression and augmenting immune responses.
  • Monoclonal antibodies targeting NR2F6 have demonstrated efficacy in preclinical studies, modulating immune checkpoints and rejuvenating exhausted T cells. The development of antibody-drug conjugates and bispecific antibodies adds a layer of versatility to NR2F6-targeted biologics, enabling innovative therapeutic strategies.
  • CRISPR/Cas9-mediated gene editing has been employed to investigate the consequences of NR2F6 knockout or overexpression in T cells, providing valuable insights into its role in immune responses.
  • Combining NR2F6-targeted therapies with established immune checkpoint inhibitors, such as anti-PD-1 or anti-CTLA-4 antibodies, represents a synergistic strategy to enhance therapeutic efficacy.

In summary, advances in NR2F6-targeted therapies underscore the transformative potential of this emerging field, and Creative Biolabs' support of academia, industry, and healthcare providers driving advances in NR2F6-targeted therapies is helping to realize the full potential of NR2F6 as a therapeutic target.


  1. Zhao, Linjie, et al. "Nuclear receptors: recent drug discovery for cancer therapies." Endocrine Reviews 40.5 (2019): 1207-1249.

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