Abstract B057: Caloric restriction disrupts the xenobiotic AhR/Nrf2 detox circuit to reverse early immune tolerance in ovarian cancer

Abstract Ovarian tumors exploit the xenobiotic-responsive aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2–related factor 2 (Nrf2) detoxification circuit to establish early immune tolerance and suppress antitumor immunity. This redox-governed axis integrates signals from host metabolism, tumor oxidative stress, and microbial ligands to shape the immune microenvironment. In our prior work, we implemented 30% caloric restriction (CR) as a systemic metabolic intervention in immunocompetent murine models of ovarian cancer. CR significantly delayed tumor progression and prolonged survival, with effects extending beyond nutrient deprivation alone. These outcomes were accompanied by extensive reprogramming of the tumor immune microenvironment, shifting from an immune-silent to a cytotoxic and pro-inflammatory state. To elucidate the underlying immunometabolic mechanisms, we performed integrated plasma metabolomics and RNA sequencing on tumors and myeloid populations. CR lowered circulating levels of immunosuppressive metabolites including kynurenine, indoxyl sulfate, and asymmetric dimethylarginine (ADMA), which are known to activate AhR signaling, inhibit nitric oxide synthesis, and impair T cell function. This reduction is expected to limit substrate availability for xenobiotic-sensing transcriptional programs, thereby attenuating metabolite-driven immune suppression. Transcriptomic profiling of tumor-educated macrophages revealed a CR-driven shift toward a pro-inflammatory phenotype, characterized by increased expression of genes involved in T cell recruitment, antigen presentation, and interferon signaling. At the same time, key Nrf2-regulated antioxidant and detoxification enzymes such as NAD(P)H:quinone oxidoreductase 1 (Nqo1) and glutathione peroxidase 7 (Gpx7) were downregulated, indicating compromised redox buffering capacity and heightened sensitivity to immunogenic stimuli. In tumors, CR induced a transcriptional landscape favoring immune activation, marked by upregulation of dendritic cell activation markers such as integrin alpha X (Itgax/CD11c) and cytotoxic effectors such as killer cell lectin-like receptor subfamily K member 1 (Klrk1/NKG2D), along with downregulation of immunosuppressive enzymes such as prostaglandin-endoperoxide synthase 2 (Ptgs2) and tribbles pseudokinase 3 (Trib3). These changes indicate a collapse of the tumor’s immunosuppressive barrier under CR pressure. In summary, 30% CR dismantles a metabolically governed immune evasion circuit in ovarian cancer by depleting immunosuppressive metabolites, impairing redox detoxification, and activating immune-stimulatory programs. These findings define a diet-sensitive vulnerability that can be leveraged for immunoprevention and early therapeutic intervention. Citation Format: Amirhossein Mohseni, Mary P. Udumula, Sedigheh Taghinezhad-S, Mohammed Husain M. Bharmal, Km Anjaly, Joey L. Guy, Miriana Hijaz, Shailendra Giri, Ramandeep Rattan. Caloric restriction disrupts the xenobiotic AhR/Nrf2 detox circuit to reverse early immune tolerance in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B057.