Metformin suppresses PPARδ-driven CD47 transcription to enhance macrophage phagocytosis in lung cancer

Metformin, an activator of AMP kinase, influences critical cellular processes, including proliferation, metabolism, inflammation, and immunity. However, its specific impact on macrophage-mediated phagocytosis of tumor cells remains poorly characterized. Our study demonstrates that metformin treatment substantially decreases both CD47 protein and mRNA levels in lung cancer cells. This reduction stems from metformin's suppression of CD47 gene transcription. Consequently, metformin enhances macrophage phagocytic activity against cancer cells. In vivo analyses using a tumor implantation model revealed that metformin impedes tumor immune escape. This effect correlates with diminished CD47 expression within tumors and heightened macrophage phagocytosis. Furthermore, combining metformin with an anti-CD47 antibody synergistically augmented antitumor immunotherapy efficacy. Mechanistically, metformin attenuates peroxisome proliferator-activated receptor delta-mediated CD47 transcriptional activation and subsequent gene expression. These results elucidate a novel mechanism by which metformin counteracts tumor immune evasion.