PhD Candidate University of Wisconsin-Madison Madison, Wisconsin, United States
Disclosure(s):
Fei Sun, PhD: No financial relationships to disclose
Introduction/Rationale: FXR is best known for regulating bile acid metabolism but also has emerging immune functions. How FXR influences tumor-associated macrophages (TAMs) in colorectal cancer is still unclear. Because TAM-driven immune programs strongly affect tumor progression, defining whether FXR shapes macrophage-mediated tumor immunity is biologically and therapeutically important. We examined whether pharmacologic FXR activation enhances anti-tumor macrophage activity and whether these effects require macrophage-intrinsic FXR.
Methods: To evaluate FXR gain-of-function, mice in CT26 and AOM-DSS Colitis-associated CRC models were treated with the FXR agonist obeticholic acid (OCA). To test loss-of-function, macrophage-specific FXR-deficient mice (Fxrfl/fl;Cx3cr1-Cre) were generated. Tumor burden, proliferation, and gene expression were examined by caliper measurement, histology, and qPCR. TAM states were analyzed by flow cytometry to quantify M1-like versus M2-like markers, co-stimulatory molecules, and antigen-presentation capacity.
Results: FXR activation significantly reduced tumor size and weight in both CT26 and AOM–DSS models. OCA treatment downregulated key oncogenes, decreased proliferative markers, and hifted TAMs toward an immunostimulatory profile, with increased M1-associated markers, enhanced co-stimulatory signaling, and elevated antigen-presentation pathways. In contrast, macrophage-specific FXR loss markedly accelerated tumor growth, increased spleen weight, heightened oncogene expression, and drove TAMs toward an immunosuppressive, M2-like phenotype with reduced antigen-presentation ability.
Conclusion: These findings identify macrophage FXR as a critical regulator of tumor immunity in CRC. FXR activation enhances anti-tumor macrophage programming and suppresses tumor progression, while macrophage-intrinsic loss of FXR impairs immune activation and promotes tumor growth. FXR represents a promising therapeutic target for reconditioning the tumor microenvironment in CRC.
