Growth differentiation factor 11 reprograms M2-like macrophages: Targeting immunometabolism for cancer therapy

Figure 1 Growth differentiation factor 11-mediated immunometabolic reprogramming drives macrophage re-education and suppresses tumor aggressiveness. This figure is a mechanistic diagram showing how growth differentiation factor 11 (GDF11) treatment flips pro-tumoral macrophages into an anti-tumoral state, based on findings primarily in the hepatocellular carcinoma context. The baseline (left) shows an M2-like tumor-associated macrophage (pro-tumoral) characterized by small, dysfunctional mitochondria (low oxygen consumption rate), high cholesterol (lipid droplets), and high cluster of differentiation (CD) 206. It secretes pro-tumoral factors [interleukin (IL)-6, angiogenin] that promote cancer cell proliferation and migration. GDF11 treatment (center) leads to the GDF11-re-educated macrophage (anti-tumoral) on the right. Signaling through Smad2/3 triggers immunometabolic reprogramming, resulting in large, functional mitochondria (high oxygen consumption rate), reduced cholesterol, loss of CD206, and high reactive oxygen species production. This re-educated macrophage secretes anti-tumoral factors (tumor necrosis factor-alpha, IL-1beta), which effectively inhibit cancer cell proliferation and migration. TAM: Tumor-associated macrophage; CD: Cluster of differentiation; GDF11: Growth differentiation factor 11; OCR: Oxygen consumption rate; ROS: Reactive oxygen species; IL: Interleukin; TNF: Tumor necrosis factor.