Clofibrate inhibits tumor immune escape by increasing macrophage phagocytosis

The CD47/SIRPα signaling axis functions as a critical innate immune checkpoint, enabling tumor immune escape. Although the PPARα Agonist clofibrate is known to influence Cancer cell metabolism, proliferation, and inflammatory responses, its specific effect on macrophage-mediated phagocytosis of Cancer cells has not been determined. In this study, we found that clofibrate downregulates CD47 in lung Cancer cells through reductions in gene expression, membrane protein levels, and transcriptional activity. This downregulation thereby promoted macrophage phagocytosis. Using in vivo tumor models, we further demonstrated that clofibrate limits immune escape and exhibits significantly enhanced anti-tumor efficacy when combined with an anti-CD47 antibody. Mechanistically, the inhibition of CD47 by clofibrate was dependent on PPARα, as evidenced by its reversal upon PPARα silencing. Together, these results uncover a novel mechanism through which clofibrate restricts tumor immune escape by transcriptional suppression of CD47.

CD47; Clofibrate; Immune escape; Phagocytosis; Transcription.