Chlorogenic Acid Regulates Macrophage Polarization in LUAD by Inhibiting Taurodeoxycholic Acid Metabolism to Block the TGR5 / STAT3 Signaling Pathway

Lung adenocarcinoma (LUAD) poses a leading cause of cancer-related mortality, necessitating the need for effective and less toxic therapies. Chlorogenic Acid (CGA), a naturally occurring polyphenol, has attracted attention for its potential anti-tumor properties, but its efficacy and mechanisms in LUAD require thorough investigation. To evaluate CGA's potential, we conducted a comprehensive study in a LUAD mouse model. We performed CT scanning and histopathological analysis to confirm its dose-dependent inhibition of tumor growth. Body weight monitoring assessed its lower systemic toxicity compared to cisplatin. Flow cytometry revealed CGA's unique ability to reprogram tumor-associated macrophages by reducing immunosuppressive M2 polarization and promoting anti-tumor M1 phenotypes. Metabolomic profiling identified a significant reduction in the pro-tumor metabolite taurodeoxycholic acid (TDCA) upon CGA treatment. Subsequent in vitro co-culture studies and western blot analysis demonstrated that CGA disrupts the TDCA-activated TGR5/STAT3 signaling axis, which is crucial for M2 macrophage polarization. Our findings unveil a novel immunometabolic mechanism through which CGA suppresses LUAD by remodeling the tumor microenvironment, highlighting its promise as a therapeutic agent or adjunct with both efficacy and a favorable safety profile.