Polyphenols as Modulators of Macrophage Polarization: Mechanisms and Therapeutic Potential in Chronic Inflammatory...

Macrophage polarization between pro-inflammatory M1 and anti-inflammatory M2 phenotypes is pivotal in chronic inflammatory diseases, offering a key therapeutic target. Natural polyphenols exhibit promising immunomodulatory capacity. This review illustrates how polyphenols target key signaling pathways (NF-κB, JAK/STAT, PI3K/Akt, and Notch) to subsequently direct macrophage polarization, and reveals their potential therapeutic effects in chronic inflammatory diseases. The literature was collected from the Web of Science and PubMed databases using relevant search terms, such as "natural polyphenols," "macrophage polarization," "natural products," "signaling pathways," "chronic inflammation," "anti-inflammatory," and "pharmacokinetics." Polyphenols exert their effects by modulating core signaling pathways, with the resultant reprogramming of macrophage polarization being a key consequential event. These compounds primarily promote M2 polarization, thereby resolving chronic inflammatory-related diseases, including atherosclerosis, metabolic diseases, and neurodegenerative diseases. Meanwhile, their ability to induce M1 polarization also provides new intervention strategies for cancer therapy. In addition to overcome the limitations of low bioavailability and low toxicity of polyphenols, this review proposes innovative approaches including nanotechnology, synthetic biology, and artificial intelligence. Polyphenols modulate macrophage polarization via signaling pathways, demonstrating therapeutic duality: promoting M2 polarization to resolve chronic inflammation while inducing M1 polarization for cancer immunotherapy. This insight positions them as promising immunomodulators.