Özmert, Enis

Abstract Background: Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy with limited treatment options. CCA exhibits a distinct desmoplastic and tolerogenic tumor immune microenvironment (TIME) characterized by elevated bile acid concentrations resulting from obstructive cholestasis and dysregulated bile acid metabolism. TGR5 is an essential component of bile acid signaling. We hypothesize that bile acids promote CCA progression by establishing an immunosuppressive TIME through TGR5 signaling, which can be therapeutically targeted using SBI-364, a novel potent small molecule TGR5 inhibitor. Methods: Single-cell RNA sequencing (scRNA-seq) of immune cells from human intrahepatic (iCCA) and perihilar (pCCA) CCA tumors were conducted. Therapeutic studies were performed using syngeneic murine models of iCCA (PMID: 38458319), a novel syngeneic model of pCCA, and patient-derived xenograft (PDX) models. In collaboration with Sanford Burnham Prebys, SBI-364, a first in-class competitive TGR5 antagonist, was assessed in vivo. Additionally, we performed co-culture experiments with bile acid +/- SBI-364-treated murine bone marrow-derived monocytic myeloid-derived suppressor cells (M-MDSCs) and CD8+ T cells to assess functional immunosuppressive effects. Results: Human scRNA-seq revealed significantly increased TGR5 (GPBAR1) expression predominantly in myeloid cell populations within the CCA TIME. SBI-364 treatment significantly reduced tumor burden in both syngeneic orthotopic iCCA models and a novel pCCA model that recapitulates the anatomic characteristics of perihilar CCA. In contrast, NOD/SCID mice bearing PDX535 (predicted sensitive) and PDX136 (predicted resistant), SBI-364 treatment did not achieve tumor reduction, suggesting that TGR5 inhibition predominantly attenuates tumor progression through modulation of bile acid-immune cell interactions. SBI-364 treated murine tumors had a significant reduction in immunosuppressive macrophages expressing interleukin-10 and M-MDSCs compared to vehicle treated tumors. Furthermore, bile acid-treated M-MDSCs exhibited enhanced suppression of CD8+ T cell proliferation and function, an effect that was abrogated by SBI-364 co-treatment. Conclusion: We demonstrate that TGR5 inhibition represents a promising therapeutic strategy across multiple immunocompetent preclinical CCA models. We demonstrate that the bile-acid TGR5 axis promotes CCA progression via immunosuppressive myeloid cells. Specifically, TGR5 signaling potentiates the immunosuppressive capacity of M-MDSCs, contributing to an immunosuppressive niche that facilitates tumor progression. These results establish TGR5 as a rational therapeutic target for overcoming immune evasion in cholangiocarcinoma. Citation Format: Enis Hikmet Ozmert, Binbin Li, Jingchun Yang, Hannah Elizabeth Stumpf, Jessica R. Willhite, Danielle Carlson, Jennifer L. Tomlinson, Jon Covel, Raghuveer Ramachandra, Steven Olson, Rory L. Smoot, Sumera Ilyas. Therapeutic targeting of TGR5 abrogates bile acid driven myeloid cell immunosuppression in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2896.

Hepatitis D virus (HDV) infection remains a major cause of severe liver disease among hepatitis B virus (HBV)-infected patients, contributing to accelerated progression to cirrhosis and hepatocellular carcinoma. Pegylated interferon-α remains the first-line therapy for chronic HDV infection in most cases. However, despite its approval for HBV and hepatitis C virus (HCV) infections, its use in HDV is largely driven by a lack of other options and is constrained by its limited efficacy, suboptimal durability of response, and a substantial side effect profile. Meanwhile, bulevirtide, an entry inhibitor, became the first agent to be approved for use in chronic HDV infections by the European Medicines Agency (EMA), and several other therapies are currently being investigated as well. In this review, we provide updates on recent advancements in HDV treatment and novel therapies.