XCT-790

Estrogen-Related Receptor Alpha (ESRRA) is an orphan nuclear receptor that plays a pivotal role in regulating cellular metabolism, mitochondrial biogenesis, and energy homeostasis through transcriptional control. It has been implicated in diverse physiological processes and diseases, including cancer. However, the transcriptional programs governed by ESRRA and the underlying molecular mechanisms remain incompletely understood. Here, we demonstrate that ESRRA serves as a central regulator in orchestrating the transcriptional activation of estrogen receptor α(ERα)-occupied super enhancers (ERSEs) and cognate ERα -target genes. In parallel, ESRRA represses the expression of cytosolic RNA sensors RIG1 and MDA5, thereby attenuating type I interferon (IFN) signaling and type I IFN-stimulated genes. In terms of mechanism, ESRRA is recruited to ERSEs together with ERα in response to estrogen and their binding to ERSEs occurs in a mutually dependent manner. In contrast, ESRRA directly binds to the promoter regions of RIG1 and MDA5 to suppress their expression. Consistent with these findings, pharmacological inhibition of ESRRA using its inverse agonist XCT790 suppressed estrogen/ERα-induced gene transcription while enhancing type I IFN pathway and antitumor immunity, thereby restraining ERα-positive breast cancer cell growth both in vitro and in vivo. Combination treatment with XCT790 and endocrine therapies, including the ERα antagonist Tamoxifen or degrader Fulvestrant, produced synergistic antitumor effects. Furthermore, co-treatment with XCT790 and tamoxifen re-sensitized Tamoxifen-resistant ERα-positive breast cancer cells to Tamoxifen treatment. In addition, XCT790 treatment augmented the therapeutic efficacy of chemotherapeutic agents such as Doxorubicin in suppressing ERα-positive breast cancer cell growth both in vitro and in vivo. In summary, our findings reveal that ESRRA is a pivotal regulator of ERSEs and estrogen/ERα-target gene activation, as well as the type I IFN signaling pathway, highlighting its potential as a promising therapeutic target in ERα-positive breast cancer in the clinic.

Endometrial cancer (EC) is a female malignancy closely linked to metabolic dysregulation. Most patients with EC exhibit poor responses to immunotherapy, underscoring the need to identify novel therapeutic targets at the intersection of metabolism and immune regulation.

In vitro: integrated proteomics, CUT&Tag (cleavage under targets and tag mentation) sequencing, dual-luciferase reporter assays, lipidomic profiling, and macrophage-tumor co-culture systems collectively demonstrated estrogen-related receptor (ERR) α’s dual metabolic-immunomodulatory role in KLE and HEC-1A human cell lines. Patient-derived organoids were used to validate the therapeutic efficacy of ERRα targeting. In vivo, the KLE cell xenograft model was used to evaluate tumorigenicity and therapeutic efficacy in mice. In humans, a retrospective cohort of 166 patients with EC was analyzed by immunohistochemistry (IHC) to quantify ERRα expression and macrophage infiltration, establishing clinical correlations and therapeutic implications. Spatial analysis of M2 macrophages in EC progression was performed using multiplex IHC.

In EC cells, ERRα transcriptionally upregulates protein tyrosine phosphatase mitochondrial 1 through direct promoter binding (-624 to −609 bp). This interaction promotes cardiolipin biosynthesis, thereby stabilizing mitochondrial inner membrane ultrastructure, enhancing oxidative phosphorylation activity, and elevating reactive oxygen species (ROS) levels. Subsequently, ROS activates the NF-κB signaling axis, inducing CCL2 secretion to recruit M2 macrophages into the tumor microenvironment. Importantly, combined inhibition of ERRα (using XCT790) and CCL2 (using carlumab) significantly enhanced antitumor efficacy in EC. Additionally, ERRα expression in EC tissues may serve as a clinical indicator for disease evaluation.

This study uncovers a pivotal role of the ERRα metabolic axis in reshaping the EC immune microenvironment, providing the mechanistic evidence linking mitochondrial lipid metabolism to macrophage-driven immunosuppression. Our findings establish a theoretical foundation for developing combination therapies targeting metabolic-immune crosstalk, offering a strategy to overcome immunotherapy resistance in EC.