Wenxia Changfu formula inhibits Lewis lung cancer metastasis by reprogramming tumor-associated macrophages through the PPAR-γ/CD36 pathway.

Background: Wenxia Changfu formula (WCF), a traditional Chinese herbal medicine, has shown therapeutic potential for treating lung cancer in clinical practice. Metastasis is the main cause of mortality in lung cancer patients, reprogramming tumor-associated macrophages (TAMs) represents a promising strategy.

Objective: This study aims to investigate the effects of WCF on metastasis of Lewis lung cancer (LLC) cells and to elucidate the underlying mechanisms.

Methods: RAW264.7 cells were differentiated into M2 macrophages, and conditioned medium from macrophages with different interventions was used to culture LLC cells. The effects of WCF on tumor migration and invasion were evaluated. Specific markers of macrophage polarization, non-targeted metabolomics, lipid content, and the PPAR-γ/CD36 pathway in macrophages were analyzed. To investigate the in vivo effects of WCF on metastasis, a mouse model was established using LLC-luciferase (LLC-Luc) cells, macrophages were depleted upon clodronate liposome administration.

Results: WCF effectively inhibited M2-like polarization of macrophages, as evidenced by reduced expression of CD206 and Arg-1, while promoting M1-like polarization, with increased expression of CD86, IL-1β, and TNF-α. These changes were correlated with decreased migration and invasion of LLC cells. In vivo, WCF treatment significantly decreased the fluorescence intensity of LLC-Luc cells, with no significant difference observed between WCF and clodronate liposome interventions. Furthermore, WCF regulated fatty acid metabolism, decreased lipid accumulation, and suppressed the PPAR-γ/CD36 pathway in M2 macrophages.

Conclusions: WCF inhibits the metastasis of LLC cells by reprogramming TAMs, mediated by the PPAR-γ/CD36 pathway and fatty acid metabolism.