Abstract 3135: First-in-class NR2F6 antagonist TES-ONC-07 enhances anti-cancer host immunity reducing tumor growth in a “cold” cancer model

Abstract Anti-cancer immunotherapy has been a groundbreaking approach in the oncology field. However, currently approved immune checkpoint inhibitors (ICI) suffer from several drawbacks, such as low patient response rate and acquired resistance. The reasons why certain patients do not respond to ICI have not been fully elucidated. Recently, the high expression of the orphan Nuclear Receptor Subfamily-2 Group-F Member-6 (NR2F6) has been suggested as a biomarker for ICI sensitivity in melanoma patients (Kim H. et al. Science, 2023). NR2F6 expression correlates with low IFNγ signature and response to anti-PD-1. In T cells, NR2F6 acts as a transcriptional repressor of specific cytokines (IL-2, IFNγ), pivotal for anti-tumor response. Thus, NR2F6 is a pivotal factor that limits immune infiltration and activation in the tumor microenvironment. So far, the evaluation of NR2F6 as a potential drug target has been limited by the lack of small molecule ligands. A Tes Pharma drug discovery project has led to the identification of TES-ONC-07, an orally available first-in-class NR2F6 antagonist. TES.ONC-07 binds NR2F6 recombinant protein in the nanomolar range. TES-ONC-07 binding to NR2F6 leads to the detachment of the nuclear receptor from the promoter of target genes such as IL-2. Ex vivo, TES-ONC-07 stimulation increases the production of specific cytokines, including IL-2 and IFNγ, when added to CD4+ and CD8+ T cells. In a melanoma B16-F1 mouse model, TES-ONC-07 increases infiltration of several myeloid and lymphoid cell subsets, resulting in a significantly reduced cancer growth. Finally, we demonstrated that orally administered TES-ONC-07 has antitumor activity. In conclusion, we have identified the first small molecule NR2F6 antagonist endowed with characteristics that allowed in vivo proof of concept. TES-ONC-07 administration leads to increased immune infiltration in a notably “cold” cancer model and this effect remarkably slows down cancer growth. Overall, our data suggests that NR2F6 is a valuable novel drug target. Potentially, treatment with TES-ONC-07 may increase sensitivity to ICI, also in those patients with limited response. Further studies are ongoing to test combination therapies as well as complete the preclinical development of TES-ONC-07. Citation Format: Francesco A. Greco, Daniela Passeri, Gianmario Ciaccioli, Cipolloni Marco, Carolina Colliva, Cristina Geroni, Paride Liscio, Emiliano Rosatelli, Giorgia Manni, Francesca Fallarino, Giuseppe Damiano, Vincenzo Russo, Roberto Pellicciari. First-in-class NR2F6 antagonist TES-ONC-07 enhances anti-cancer host immunity reducing tumor growth in a “cold” cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3135.