Plant-derived active pharmaceutical ingredients target macrophage polarization and phagocytosis and reprogram systemic metabolism toward anti-melanoma metastases

Melanoma is the most aggressive form of skin cancer, with approximately 50% of cases harboring BRAF mutations, contributing to high metastatic potential and poor prognosis. BRAF inhibitors, such as vemurafenib (PLX4032), are used in late-stage melanoma; however, acquired resistance and adverse effects limit their efficacy. This study identified active pharmaceutical ingredients (API) from a medicinal Asteraceae plant (designated BC) using a bioactivity-guided approach which shows potent anti-metastatic effects on melanoma lung metastasis. The BC_API significantly inhibited the epithelial-mesenchymal transition phenotype, reduced cancer stem-like characteristics, and induced apoptosis in metastatic melanoma cells. In a high-propensity lung metastatic A375LM eIF4g/Luc xenograft mouse model, treatment with PLX4032 (50 mg/kg) and BC_API (20 mg/kg) suppressed lung and liver metastases and extended animal survival to 40 and 34 days, respectively, compared to 26 days in control mice. In the lung tumor microenvironment, M2 macrophages were detected abundantly in tumor nests and frontal tumor regions which were polarized into M1 macrophages after API treatment. In vitro studies further confirmed that the BC_API promoted M1 macrophage polarization and its phagocytotic ability. GC/MS-based metabolomics and KEGG-database pathway analysis showed that BC_API affected primary metabolism in tumor-bearing mice, such as unsaturated fatty acid metabolism or biosynthesis and arginine biosynthesis that might be associated with melanoma invasion/metastasis, M1 macrophage polarization, and oxylipin metabolism, contributing to the anti-tumor metastasis effect of the API. This study highlights the great potential of a phytoAPI as botanical drug candidate for metastatic melanoma therapy [ 1 ] [ 2 ]. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany